Hemorrhage is the leading cause of preventable death after trauma (1). Despite recent advancements in trauma care, uncontrolled hemorrhage is still responsible for greater than 50% of all trauma-related deaths in both civilian and military settings within 48 h of injury (2). More than half of the patients who exsanguinate after traumas do so within the first 3 h of injury (3). The acute coagulopathy of trauma (ACT) is present in at least 25% of severely injured individuals, and up to 60% of patients with severe traumatic brain injury (TBI) (4). This entity has been observed in the field before resuscitation (5–13).
Principal drivers of ACT include tissue hypoperfusion, hyperfibrinolysis, inflammation, and acute activation of the neurohumoral system (Fig. 1) (8, 9). These downstream effects occur following severe injury and/or TBI resulting in acute coagulopathy (10, 14, 15). This results in endothelial dysfunction, hyperfibrinolysis, inflammatory dysregulation, altered platelet function, and dysfibrinogemia (10). As a result, ACT has been shown to be an independent predictor of mortality (16, 17). These clinical findings are distinctly separate from trauma-induced coagulopathy (TIC) which has the additional component of iatrogenic coagulopathy resulting from crystalloid resuscitation leading to acidosis, hypothermia, and dilution (8–11, 13). Plasma has been shown to reverse coagulopathies associated with ACT or TIC and improve survival even in the absence of packed red blood cell (PRBC) transfusions (18–20). Owing to the exacerbation of hemorrhage secondary to traumatic and iatrogenic coagulopathies, optimal resuscitation designed to correct coagulopathy is crucial to survival (21, 22). Strategies currently under investigation to minimize potentially survivable deaths include early plasma utilization, determining the etiology of coagulopathy, and optimization of hemorrhage control (18). Resuscitation designed to minimize iatrogenic crystalloid resuscitation injury, correct coagulopathy, and empirically help stop bleeding is known as damage control resuscitation.
Fresh whole blood (FWB) is an amalgamation of procoagulant factors, oxygen carrying red cells, and oncotic proteins before being separated into different stored components including plasma, PRBCs, and platelets. It is different from stored whole blood which is stored for a few days before reinfusion. FWB has been shown to help mitigate coagulopathy and provide optimal hemorrhage resuscitation (23, 24). Plasma constitutes up to 55% of the total blood volume and is composed of dissolved proteins, clotting factors, electrolytes, hormones, carbon dioxide, and glucose (21). The effects of plasma that result in improved outcomes have yet to be thoroughly elucidated. There are over 1,000 proteins in plasma, many of which are biologically active and many of which have unknown functions (25). In contrast to FWB, it can be preserved via multiple mechanisms including freeze-drying (1). Freeze-dried plasma (FDP) was used in World War II (WWII), but was subsequently discontinued, due to risk of blood borne disease transmission including hepatitis (26).
Although FWB is preferred as it contains all blood components, it is not always feasible in the operational environment and it is rarely used in the civilian setting (27). In the United States alone, the utilization of fresh frozen plasma (FFP) has increased over the last two decades from 2.3 million units of FFP in 1991 to 4.5 million units by 2008 (28, 29). There is a growing use of thawed plasma prepared from FFP that can be kept for up to 5 days (30–32). Currently, dried plasma is used for damage control resuscitation and as a primary resuscitation fluid by the Israeli Defense Forces, French special-forces, in South Africa and in Germany where dried plasma is also used in the civilian setting (18, 27, 30, 31). Even with this worldwide increase in usage, and associated benefits, there are logistical and historical safety concerns that have limited the widespread use of plasma both inside and outside of the hospital setting (26).
Early prehospital administration of plasma offers several significant advantages over current resuscitation fluids (21, 33, 34). These include reduction of crystalloid infusion, thereby avoiding dilutional coagulopathy, improved endothelial function, physiological pH, and improved maintenance of intravascular volume (18, 21). Depending on the formulation, plasma also has the benefits of easier storage and reduced logistical constraints compared with FWB (18, 21, 27).
Several recent large multicenter studies have shown that balanced resuscitation of plasma:PRBCs can decrease mortality, decrease total blood product resuscitation requirements, and reduce complications in patients undergoing massive transfusions (3, 35–37). Multiple other studies have shown early plasma resuscitation to be safe and beneficial (21, 34, 37, 38). In response, the American College of Surgeons Trauma Quality Improvement Project issued guidelines in November 2013 for trauma resuscitation recommending “Universal donor products should be immediately available on patient arrival to support a ratio-based transfusion” (39).
This article will review the use of plasma to improve resuscitation of severely injured trauma patients by analyzing the current literature involving plasma types, historical transitions in utilization schema, effects on coagulation factors when stored, coagulation benefits, lyophilized plasma (LP), novel methods of reconstitution, and areas of future research.
HISTORICAL SYNOPSIS ON PLASMA USE—FULL CIRCLE
1918 to WWII
In a 1918 editorial in the British Medical Journal, Capt. Gordon Ward recognized plasma for its possible therapeutic benefit. He highlighted the clinical interest in safely treating patients with active hemorrhage while mitigating negative transfusion reactions: “Surely this difficulty might be avoided by not transfusing the corpuscles at all, but only citrated plasma, which would be easy to keep and easy to give … A man apparently dying from haemorrhage is not dying from lack of haemoglobin, else severe cases of anaemia would die long before they do, but from draining away of fluid, resulting in devitalization and low blood pressure.” He therefore called for a trial comparing citrated plasma to whole blood (40).
There have been a number of physicians and scientists who have investigated various properties of human plasma. Dr Max Strumia initiated some of the earliest work with plasma in 1927 and subsequently experimented with turning the liquid into a sterile powder. He spent a significant amount of his career refining the freeze-drying of biologic materials and invented a small apparatus capable of shell freezing liquid plasma (LQP) and drying it under a vacuum (26). He presented his findings at the 1940 AMA meeting. His first publications on intravenous plasma transfusion recognized the early work of Dr John Elliott.
In 1936, Dr Elliott first introduced the idea of using plasma as a substitute for whole blood when he presented “A Preliminary Report on a New Method of Blood transfusion.” He used a vacuum bulb-tube with citrated anticoagulant and perforations for RBCs and plasma removal (41). He recommended this newfound plasma for the treatment of “traumatic shock.” Ongoing experimentation with Baxter laboratories yielded the TransfusoVac bottle which replaced the antiquated storage beakers (26). This standard blood collection container was widely used throughout WWII until the universal adoption of plastic blood storage bags occurred in the 1970s.
The stage was set for novel plasma products in July 1940 when Britain was under aerial attack, forcing British military leaders to call upon the American Red Cross to ship plasma directly to London (26, 42). By September 1941, the Committee on Blood Substitutes of the National Research Council accepted both LQP and FDP as new therapeutics (43). Packaged kits using distilled water for reconstitution of the dried plasma were designed for battlefield infusions (26, 42). Under the “Blood for Britain Campaign” in New York City from 1940 to 1941, more than 14,556 units of blood were donated, with the majority being processed into plasma units (42). The program was halted in January 1941 because many of these units were plagued by sterilization difficulties resulting in bacterial contamination that became evident during shipment overseas (26, 42).
Between 1942 and 1945 the American National Red Cross collected over 13 million units of blood (26). More than 12 million units were converted to plasma with the majority of RBCs being discarded (26). During ramp-up to large-scale commercial production, much of the plasma was created from large donor pools. WWII, often called “The Plasma War,” saw the transfusion of plasma fall out of favor after its association with “serum hepatitis” (26). By the end of WWII, more than 40,000 pints of whole blood were transfused during the final battle at Okinawa (26, 44). Eventual usage during the Korean War solidified the harmful effects of hepatitis transmission, effectively terminating widespread use of pooled plasma for the next 30 years (26).
The Vietnam War to 2001
The experience with resuscitative fluid research leading up to the Vietnam War in 1965 to 1973 was closely tied to the associated decline in plasma use. Initially labeled Da Nang lung in Vietnam, and later renamed Acute Respiratory Distress Syndrome, the inflammatory effects of crystalloid and colloid resuscitation plagued ongoing physiological resuscitation efforts for decades (5, 45–50). Eventually, a possible explanation showed crystalloid resuscitation increased neutrophil activation, immune dysfunction, and ischemia-reperfusion injury (50, 51).
By the beginning of the 1990s, solvent/detergent (S/D) was used by the German Red Cross Blood Service West (GRCS-W) to make lyophilized pooled plasma safer after 20 years of stagnation (30). This major step forward in safety was later abandoned due to risk of prion disease transmission; however, there were no reported transfusion transmissions (52). There were more than 300,000 units of S/D-treated plasma used before transition to single-donor quarantined plasma in 2007 (30).
The Afghanistan and Iraq War to present
The negative effects of crystalloid resuscitation became well known during this period. In a 2004 swine hemorrhage model, crystalloid was shown to increase dysfunctional inflammation compared with whole blood (53). Further research has elucidated differential effects on Toll-like receptors in rat hemorrhage models demonstrating increased inflammation, hyperchloremic acidosis, fluid overload, and inappropriate hypertension (54). These findings challenged the long-standing concept of crystalloid infusion, and even component therapy, compared with FWB.
In 2007, the GRCS-W transitioned to using single-donor FDP made from quarantined plasma for civilian use. This single-donor processing approach is still being used today (Fig. 2) (30). Quarantined plasma is stored and frozen after donation for at least 4 months and is used only after negative tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), hepatitis A virus (HAV), and PVB-19 (30). Since introduction in 2007 more than 230,000 units had been delivered under the name LyoPlas N-w (German LPN-W) by 2013, with a safety profile comparable to FFP (30).
Also in 2007, Borgman et al. reviewed 246 combat casualties who required massive resuscitation. He demonstrated an association between plasma:PRBCs with a ratio approaching 1:1 and improved survival (55). Similar findings have been independently demonstrated in multiple studies (3, 35–38, 55–60). For these reasons, early plasma therapy is considered critical for the treatment of ACT (18, 22), though other studies have questioned these benefits (61, 62). These studies used FFP for resuscitation and were retrospective in nature. Therefore, the possibility of survival bias could not be excluded due to the time required for thawed plasma to be available. Survival bias occurs in these studies because patients who live longer are able to receive more transfusions, which result in a higher ratio of plasma to PRBC. Thus, it is not clear if high ratios result in improved survival or if living longer results in a higher ratio.
In 2013, the civilian Prospective Observational Multicenter Massive Transfusion Trial (PROMMTT) was published in an attempt to eliminate survival bias. This study showed the median time to death due to hemorrhage was 2.6 h, highlighting the need for early intervention postinjury, often before completion of definitive surgical intervention (3). There was also a reduction in mortality with early and increased plasma and platelet:PRBC ratios approaching 1:1:1 (3). In 2015, the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial expanded on the work of PROMMTT, demonstrating decreased death from exsanguination in patients receiving 1:1:1 vs. 1:1:2 though there was no statistical difference in complications or overall 24-h and 30-d mortality (35).
Currently, the damage control resuscitation clinical practice guideline created by the US military and many civilian massive transfusion protocols now dictate the use of plasma, platelets, and PRBCs in a 1:1:1 ratio in an effort to reproduce the effects of FWB (18). In some settings, plasma is being used as a primary resuscitation fluid in lieu of crystalloids and colloids in patients with active hemorrhage (18, 31, 62). These results show promise for early survival benefits, and suggest that a high ratio transfusion approaching that of FWB with early plasma administration may have significant impact (19, 37, 38). The ability to store plasma in multiple forms and reduce reliance on cold-chain storage allows for reduced logistical constraints. In addition, there is improved transportability, weight reduction, and improved availability in prehospital settings including austere environments where FWB may not be safely accessed and transfused (27).
The preponderance of plasma used in the United States is in the form of FFP (32). FFP is obtained from FWB, and the separated plasma is then frozen at −20°C within 8 h of donation. FFP can then be stored for up to 1 year (Table 1) (32). The primary advantage of FFP compared with fresh plasma is the ability to store it for a prolonged period of time (30–32). Disadvantages include the 30 to 45 min required to thaw it, making it logistically difficult to maintain a balanced resuscitation in massive transfusion patients. In addition, there is a loss of coagulation factor function due to the freezing and thawing process (63, 64).
FP24 is similar to FFP except that it is frozen between 8 and 24 h after donation (Table 1) (32). FP24 was developed to combat the increased incidence of transfusion-related acute lung injury (TRALI) by allowing time for human leukocyte antigen (HLA) testing to allow removal of high risk donor plasma from the donor pool (65). Several studies have demonstrated that most clotting factor levels are well maintained in FP24, allowing it to be used interchangeably with FFP (66, 67). Once thawed, FFP can be maintained at 1°C to 6°C for up to 5 days with minimal relative degradation in clotting function activity, mitigating the logistical difficulties of maintaining a balanced resuscitation strategy (Table 1) (68, 69). Only thawed plasma prepared from FFP is approved for use by the American Association of Blood Banks (AABB) and the US Food and Drug Administration (FDA) (29).
LQP is plasma that has never been frozen. It can be maintained at 2°C to 6°C for up to 28 days per the AABB until expiration (Table 1) (32). Recent studies have compared clotting factors showing sustained profiles for up to 26 days with minimal clotting factor degradation (64). Hemostatic profiles of LQP were superior to thawed plasma, with sustained activity five times longer (64). Even with a relatively short shelf life, LQP may be considered as a potential effective option in the United States (64).
The most common preparations of dried plasma result from a freeze-drying process to make either a spray-dried plasma (SD) or LP formulation (Table 1) (30–32). The concept of concentrated hypertonic hyperoncotic FDP was first proposed in the United States by Rhee et al. in 2003 (70). The two most widely used products worldwide are German LPN-W and French FlyP (30, 31, 71). Both are based on a lyophilization process creating LP. LP has a number of positive logistical benefits over FFP and other products that require refrigeration including significantly extended storage duration, portability, flexibility with respect to storage temperature, and capability of rapid reconstitution in austere environments (18, 31, 71).
The German Red Cross transfused over 300,000 units of SD washed plasma that was discontinued due to risk of prion transmission (30). Since 2007 the German Red Cross has recorded more than 230,000 transfusions of single-donor German LPN-W with a similar incidence of major adverse reactions using LP compared with FFP (0.023%) (30, 71). These units are prepared from a single donor and require blood type compatibility (30). It can be stored for up to 15 months and is reconstituted in 200 mL of sterile water after only 10 min (Fig. 2) (30).
Meanwhile, the French Haemovigilance system has recorded more than 2,700 transfusion(s) of French FlyP with no documentation of any significant adverse effect (18, 31, 71). French FlyP is prepared from up to 11 donors, has universal major blood group ABO compatibility, and is reconstituted in approximately 6 min in 200 mL of sterile water (31). French FlyP can be safely stored for up to 24 months (Table 1) (31). This product is pathogen inactivated with the INTERCEPT system via nucleic acid intercalating agents (i.e., Riboflavin) in the presence of ultraviolet light. This allows inactivation pathogen nucleic acids while permitting the nucleic acid-free constituents in plasma and proteins to function (71).
Both French FlyP and German LPN-W have the advantage of being easily stored at temperatures up to 25°C in large quantities. They are quickly reconstituted for immediate use in austere conditions or level 1 trauma centers as primary resuscitation fluids, or to facilitate more balanced damage control resuscitation (18, 30, 31, 71). Improved logistical profiles have accelerated research into various plasma infusions at the point of injury.
There are a number of other plasma formulations still in clinical use. These include solvent detergent plasma that is washed, and SD that can be based on either solvent detergent plasma or LQP (32). SD has been developed as an alternate processing method to LP. The resultant product is also low volume and lightweight, similar to LP. Shuja et al. in 2011 reported using SD in a hemorrhagic swine model reconstituted to 1/3 original volume, without a compromise in coagulation properties (73). Further testing demonstrated improved survival of swine resuscitated with SD compared with Hextend or valproic acid over 7 days without any long-term organ dysfunction or complications (74). A significant amount of recent research is focusing on the individual coagulation parameters of plasma formulations, including SD (64, 73, 75–77).
RISKS OF TRANSFUSION
The utilization of plasma has significantly increased over the last two decades in the United States and worldwide, whereas transfusion-associated risks have decreased and also dramatically shifted over time (28, 65, 78). Risks of transfusion are present with all blood products including plasma. The preponderance of the data regarding plasma transfusion risks is based on FFP (65).
Although some studies have shown an increase in risk of acute respiratory distress syndrome (ARDS) with FFP transfusion, a study evaluating the incidence of ARDS in UK transfused combat casualties published in 2013 showed that the use of high ratios of plasma:red cell concentrate did not seem to affect the observed incidence of ARDS (79). Risks of French FlyP and German LPN-W have also been shown to have an equal incidence compared with FFP (30, 31). In a review of French FlyP in a combat support hospital in Afghanistan, no adverse events were reported and the product was shown to effectively reduce the prothrombin time (31). In a more extensive evaluation, the German national authority for blood products found that the incidence of urticaria, severe hypotension including anaphylactic shock, and bronchospasm were not significantly different (30). Therefore, LP seems to have an equivalent safety profile to FFP, whereas SD formulations are still being evaluated.
Historical risks were closely related to the pooled plasma processing used for manufacturing plasma during WWII. The prevalence of HBV and HCV made infectious seroconversion commonplace, especially during massive resuscitation (26). Subsequent emergence of HIV only served to increase risks associated with plasma-based resuscitation (80). The incidence of HBV infection among blood donors has decreased over time, from 1:121,000 in 1997 to 1999, to approximately 1:388,000 in 2006 to 2008 (81). Further studies have shown a frequency of confirmed donor seropositivity for HIV, HCV, hepatitis B virus surface antigen, and human T-Cell lymphotropic viruses (/100,000) to be 1.41, 7.83, 2.04, and 0.28, respectively (80). Additional system-based protections have evolved to mitigate transmission of these infectious agents by using quarantined single-donor plasma that is retested before processing using polymerase chain reaction and nucleic acid testing of samples (30, 80). HBV vaccination of the population also provides population-based protection (81). Therefore, the resultant risk of acquiring HIV, HCV, and HBV through present-day transfusion is 1:1,467,000, 1:1,149,000, and 1:280,000 donations, respectively (80, 81).
In other contemporary reviews, complication rates have decreased with a significant change in etiology (65). Owing to improved sterile processing, associated contemporary risks include TRALI, transfusion-associated circulatory overload (TACO), and allergic/anaphylactic reactions (65). Less common risks include transmission of infections, febrile nonhemolytic transfusion reactions (FNHTRs), RBC alloimmunization, and hemolytic transfusion reactions (65).
In 2003, TRALI emerged as the leading cause of transfusion-related mortality reported to the FDA (81–84). FFP was the most commonly implicated blood product; the risk per component was 6.9 times higher for FFP than RBCs (85, 86). TRALI is characterized by acute hypoxemia and noncardiogenic pulmonary edema occurring within 6 h of transfusion (82, 84, 87). This is distinctly different from ARDS, which is similar in clinical presentation, but occurs after 6 h and persists. Most patients recover from TRALI within 3 days with respiratory support, but 5% to 25% of cases are fatal (88, 89). The final common pathway is thought to be accumulation and activation of neutrophils within the pulmonary endothelium (65, 83, 90).
Multiple studies support the role of donor-derived HLA and human neutrophil antigen antibodies in TRALI (90–94). The odds ratio for developing TRALI is 15 (95% confidence interval [CI], 5.1–45) for patients receiving a transfusion from a donor who tested positive for leukocyte antibodies versus donors who tested negative although leukocyte antibodies contributed to approximately 80% of TRALI cases (95).
HLA antibodies and risk of TRALI are closely tied to multiparous women though it can also be found at low prevalence rates in men and nonpregnant women (65). HLA alloimmunization increases with the number of pregnancies where up to 1/3 of female donors test positive after four pregnancies (94, 96). The main step to mitigating TRALI has been to stop the production of transfusable plasma products from pregnant women, or alternatively testing donors with a pregnancy history for HLA antibodies before donation (65). According to data from the American Red Cross and the United Kingdom's Serious Hazards of Transfusion hemovigilance programs, these strategies have resulted in a reduction of TRALI incidence from approximately 1:51,000 premitigation to approximately 1:250,000 postmitigation (86, 97). Similar results have also been observed in Canada and Germany as well (98, 99).
Clinically, TACO is very similar to TRALI because it is also characterized by acute respiratory distress, hypoxia, and pulmonary edema associated with transfusion (100–102). The difference is that TACO is due to increased hydrostatic pressure from volume rather than increased capillary permeability (65, 100). There is no test to differentiate the two, though most cases improve with diuresis. Similar to TRALI, the mortality rate is approximately 5% to 15% with increasing risk with greater transfusion volumes (101, 103). Risk is increased with FFP ordered for anticoagulation reversal, extremes of age, preexisting cardiac and/or renal dysfunction, positive fluid balance, and increased infusion rates (101–104). The incidence of TACO is relatively low, ranging from less than 1% to 8%, but is increasing, and in 2010 it was the second leading cause of transfusion-related mortality (105).
The incidence of allergic transfusion reactions (ATRs) is estimated to occur between 1% and 3% of all transfusions (65) Most ATRs are mild and limited to urticaria, pruritis, and flushing. Anaphylactic reactions are associated with angioedema, bronchospasm, and hypotension with an incidence ranging from 1:18,000 to 1:172,000 transfusions (72, 106). RBCs are implicated in 45% of allergic reactions, whereas FFP and platelet transfusions constitute 24% and 30% of transfusion reactions, respectively (106). The majority of reactions are minor, requiring minimal supportive care (106). The incidence of ATR to FFP in two retrospective studies was 1:591 and 1:2,184 plasma units transfused (102, 106). The incidence rate of ATR was not statistically different between German LPN-W and FFP at 0.023% vs. 0.018%, respectively (30, 65). Inciting proteins or antigens are difficult to identify, though antibodies to human IgA play a role (65). Currently, premedication with antihistamine before transfusion is a common practice to limit the mild ATR reactions, but two randomized controlled trials indicated that premedication with antihistamine before transfusion did not decrease the incidence of ATR (106–108).
Another limited risk of transfusions includes transmission of other infections including both present and emerging etiologies (72). Bacterial contamination of FFP is rare, though it has been reported in Canada and Germany with five cases over multiple years (109, 110). Emerging infections including west nile virus (WNV), Zika virus, prion infections, and other unidentified pathogens are also important risks (72).
Other minor risks include FNHTRs, transfusion-associated graft versus host disease (TA-GVHD), and transmission of leukotropic viruses (i.e., human T-Cell lymphotropic viruses, cytomegalovirus) (65). Because FFP is considered noncellular, it is not typically associated with a risk of FNHTR, TA-GVHD, or transmission of cytomegalovirus-type viruses, though some studies have shown a significant number of WBCs contaminating plasma units (65). One retrospective study in a large US hospital reported the incidence of FNHTR for plasma at 1:4,476 likely due to the release of bioactive mediators during the freeze-thaw process for FFP (102, 111).
EFFECTS OF PLASMA
Traditionally, the benefits of plasma are thought to be primarily derived from its ability to correct coagulopathy and achieve hemostasis in bleeding patients by replacing consumed, depleted, or diluted coagulation proteins. The overall benefits of plasma are not fully understood. In addition to coagulation factors, plasma also consists of hundreds of proteins with therapeutic benefits and biological effects unrelated to coagulopathy correction (25). Some of these proteins may explain some of the benefits of plasma in hemorrhaging patients.
Hemorrhagic shock produces a number of negative effects. These include induction of a proinflammatory state, leukocyte infiltration, increased vascular permeability, endothelial basement membrane breakdown, exposure of subendothelial nonspecific initiation of coagulation, interstitial edema, and tissue hypoxia. As shown in Figure 3, the early use of plasma has been demonstrated to inhibit vascular permeability and mitigate many of these negative effects (34). The ability of plasma to treat hemorrhagic shock in preclinical studies is affected by certain parameters including the duration of time between thaw and infusion and preparation of plasma infused (63, 64, 68, 77).
Damage control resuscitation dictates early use of plasma in 1:1 or 1:2 ratios to improve outcomes (34, 37). In vitro studies have demonstrated ACT attenuation by PRBC:FFP transfusions compared with normal saline in a swine model (112). The PROMMTT clinical trial showed significantly decreased 6- and 24-h mortality in trauma patients requiring greater than 3 units of PRBC within 24 h who received a ratio of plasma:PRBC more than 1:2 compared with those who received ratios less than 1:2 (3, 37). Early administration of high ratios of FFP and platelets has also been shown to improve survival and reduce total blood component therapy requirements (60, 113).
Endothelial cells are one of the first cell type to come in contact with infused plasma. The vascular endothelium is arguably the largest organ in the body. It provides the central platform where the key processes of hemostasis, inflammation, and edema occur (114). Vascular integrity and permeability are compromised by a number of factors induced by hemorrhagic shock, including hypoxia, coagulation cascade intermediates (i.e., thrombin), and inflammatory mediators (i.e., TNFα). The collective process of endothelial injury, inflammation, vascular leak, and overall endothelial dysfunction after trauma has been called the endotheliopathy of trauma (38).
In vitro and in vivo rodent models of endothelial injury and hemorrhagic shock suggest that plasma can both repair and normalize the vascular endothelium by restoring tight junctions, restoring the endothelial glycocalyx, and inhibiting shedding of syndecan 1 (76, 115–118). These effects of plasma decrease inflammation and edema which are detrimental processes that contribute to organ failure and increased mortality (76, 115–118). Preclinical studies using rat and porcine models of hemorrhagic shock reveal that resuscitation with plasma decreases the proinflammatory state, and reduces vascular permeability and lung inflammation through stabilization of the endothelial glycocalyx when compared with artificial colloid, albumin, and lactated Ringers (53, 76, 118–120). In summary, the results of these preclinical investigations and PROMMTT support the benefits of early plasma resuscitation. Although the evidence for early plasma resuscitation is strong, there exists a multitude of plasma formulations and variable plasma storage parameters. Owing to the large variability in formulation and reconstitution fluid, it is unclear which of these is superior. It is therefore imperative to study the effects of the various plasma formulations and storage strategies in in vitro and in vivo models after hemorrhage.
IMPACTS OF STORAGE
After collection, plasma can be stored in multiple ways: as LQP, as FFP, and as LP or SD. Each storage method impacts plasma functionality in a specific fashion due to unique storage events tied to each formulation. For example, FFP must be frozen and then undergo a thawing process before use, whereas LP is dried. This section will focus on the impact of these events, specifically on the viability of protein coagulation factors and the therapeutic effectiveness of each plasma formulation.
The freeze/thaw process of FFP has been shown to impact the viability of protein coagulation factors and duration of its effectiveness. AABB guidelines state that thawed FFP is stored between 1°C and 6°C, and used within 24 h. If unused, it is relabeled and designated thawed plasma, which can be stored and used for up to 5 days (76, 121, 122). This policy reduces waste of unused plasma while allowing for its rapid administration when required in an emergency setting.
In in vitro and in vivo studies, Pati et al. in 2010 showed that FFP has beneficial effects on endothelial permeability, vascular stability, and resuscitation in rats after hemorrhagic shock (76). Thawed FFP significantly decreases endothelial cell permeability to 10.2-fold in vitro on post-thaw day 0 compared with lactated ringer's solution (LR). However, this effect is significantly attenuated to only a 2.5-fold decrease in endothelial cell permeability by post-thaw day 5 (76). In addition, thrombin generating capacity of FFP is diminished between post-thaw days 0 and 5 (76). Multiple other studies have shown that factors V and VIII decrease after 5 days of thawed FFP storage, but remain within acceptable hemostatic levels per laboratory analysis (68, 77, 123). In a separate study evaluating FFP from 30 donors, post-thaw day 0 FFP was compared with post-thaw day 5 FFP (thawed plasma stored for 5 days). After 5 days of thawed storage, FFP exhibited a 40% reduction in thrombin generation, a slower clotting response by Thrombelastogram (TEG) testing (4.3 vs. 3.2 min) and a longer delay in reaching maximum thrombus generation (5.7 vs. 4.6 min) (77). There was a significant decline in coagulation proteins including FV, VII, VIII, von Willebrand factor, and free Protein S by up to 30% (77).
Notably, there are no published studies evaluating the effectiveness of plasma storage age, age of plasma, or the ability of plasma to inhibit vascular leak on clinical outcomes. Plasma proteins are composed of very heterogeneous macromolecules. Many of these proteins can be unstable outside of their respective homeostatic milieu resulting in improper function or insolubility. Optimal storage conditions for each of the greater than 1,000 proteins in plasma have not been determined. It is well accepted that many proteins lose structural integrity and biological activity when stored at 4°C due to proteolysis, aggregation, and insolubility (124). There is a comparable reduction in clotting factor activity between the expected loss from the thawing process for thawed plasma and reconstituted LP (125, 126). Owing to these risks, standard management in basic science laboratories requires −80°C storage of proteins used in coagulation experiments (76) In addition, the thawing process used to prepare FFP has been implicated in the release of bioactive mediators and alterations in factor activity. In one retrospective study, bioactive mediators released during the freeze-thaw process were implicated in causing FNHTR (102, 111).
In 2009, noninferiority study comparing LP with FFP, Schreiber's group demonstrated that clotting factor activity was decreased by an average of 14% in reconstituted LP compared with prelyophilization plasma (125). Furthermore, LP had a similar coagulation profile, mortality rate, hemodynamic profile, and incidence of inflammatory mediator expression when compared with FFP in a combat relevant swine model of injury and uncontrolled hemorrhage (125). LP given with RBCs in a 1:1 ratio resulted in decreased blood loss compared with LP alone, FFP, and FFP with RBCs in a 1:1 ratio. LP resuscitation also resulted in decreased expression of IL-6 in this model. It was concluded that LP could be used for resuscitation of trauma patients with severe trauma and hemorrhagic shock with at least equal efficacy to FFP (125).
A second study at the same time compared FWB vs. Hextend vs. 1:1 FFP/PRBC vs. FFP alone in a highly lethal swine polytrauma model. This study used FWB versus controls and evaluated coagulation factors in vivo and in vitro. Similar coagulation profiles were seen in vitro analyzing factors II, VII, IX, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio, and fibrinogen. FFP and balanced resuscitation was found to be equivalent to FWB improving survival from 15% in the control group to 100% (19). In a follow-up study, SD reconstituted to one-third the original volume had equivalent mortality and in vivo coagulation properties to LP (73).
French FlyP, one of the common forms of LP, has been used clinically in a French military ICU in Afghanistan and demonstrates an equivalent safety profile and ease of use when compared with FFP (31). In follow-up studies, the in vitro hemostatic properties of French FlyP were compared with plasma samples before lyophilization. PT and PTT were found to be significantly increased, whereas factors V and VIII were diminished in French FlyP; however, other protein coagulation factors were preserved. TEG parameters and clot formation were also equivalent (75).
The effects of lyophilization and German LPN-W storage on coagulation factor activity have been extensively evaluated. Similar to the findings of Spoerke, a 15% reduction of factor VIII with preservation of other factors has been shown (30, 125). Furthermore, coagulation factors remained relatively stable over 24 months of storage at 4°C. However, when stored at room temperature fibrinogen showed a loss of 46% of activity at 24 months. Owing to these findings, German LPN-W now is restricted to a 15-month shelf life (30).
Further research has been done to evaluate German LPN-W after dissolution with sterile water. Clotting factors were found to decrease between 6.3% (FXI) and 14.9% (FVIII) after 6 h of storage at 4°C and between 6.3% (fibrinogen) and 24.3% (FVIII) after 6 days at 4°C (127). Protein S and FVIII decreased within 48 h to 50% and 66% of starting activity, respectively. In the first 6 h, there was less than a 10% reduction in Protein S and FVII. These findings suggest that German LPN-W is best used within 6 h after reconstitution in water when stored at room temperature (30, 127).
In total, the preponderance of evidence suggests that LP, in any formulation, preserves the majority of protein coagulation factors. There has been evidence of a statistical decrease in factors V and VIII, and a slight increase in PT and PTT. Importantly, both in vivo hemorrhage models and clinical experience have shown the safety and efficacy of LP. Furthermore, long storage duration over 1 year seems safe, and does not seem to negatively impact LP efficacy in austere environments. There are ongoing studies evaluating the optimal solution for LP dissolution.
NOVEL CONCEPTS CONCERNING RECONSTITUTION
LP and SD research is currently transitioning from proof of efficacy toward optimization of the reconstitution process. Current investigations include altering the reconstitution buffering solutions, using various antioxidants and reconstituting with low volume and high concentration formulas. On the basis of these findings, further improvements in storage parameters, factor activity, and availability in austere environments are possible.
Multiple studies to evaluate the most effective LP reconstitution fluid have been performed. LP reconstituted with water and ascorbic acid has been shown to reduce dysfunctional inflammation and oxidative DNA damage while reducing blood loss compared with FFP in a combat relevant multi-injury model in swine (128, 129). Specifically, IL-6 expression was decreased with LP reconstituted using ascorbic acid versus citric acid (129). LP dissolution using sterile water, LR, normal saline, and Hextend solutions was tested in the same multi-injury swine model. Reconstitution with sterile water and LR buffered with ascorbic acid resulted in decreased blood loss and an anti-inflammatory benefit compared with NS and Hextend (130). Further exploration by McCully et al. using high (22.5 mM), medium (15 mM), and low (7.5 mM) concentrations of ascorbic acid to reconstitute plasma to 50% of original volume showed an equivalent safety profile, without suppression of acute dysfunctional systemic inflammation at 4 h (131).
Further studies to assess the appropriate LP concentration after reconstitution have also been performed. Hemorrhage control is maintained when the volume of reconstituted fluid is reduced by 50% (130). Coagulation effects were unchanged when 50% volume was reconstituted using ascorbic acid buffering (130). Additional work focusing on SD showed similar efficacy when reconstituted to one-third original volume (73). These low-volume, hypertonic, hyperosmotic plasma formulations are ideally suited for point of injury use with early treatment of ACT.
The simple concept of replicating whole blood by infusing high ratios of plasma:PRBC in patients with hemorrhagic shock has been associated with an improvement in mortality and reduced total transfusion requirements (34, 35). The future of plasma research is bright, with a myriad of potentially rewarding endeavors. One of the first conceptual questions regarding plasma resuscitation is identification of patients who are severely injured that would benefit from early plasma resuscitation. Recent trauma research identified reduced plasma colloid osmotic pressure (COP), and serum protein was an indicator of injury severity in the absence of vital sign abnormalities. In addition, increased COP levels were associated with increased blood product transfusions and increased syndecan 1 shedding from the glycocalyx (132).
Early identification of patients requiring transfusion and stabilization of the glycocalyx strengthens the present argument for an expanded prehospital plasma infusion strategy (34, 38). Appropriate selection of patients in hemorrhagic shock is paramount to optimize safety of prehospital transfusions and prevent overuse by emergency medical services personnel. Safety and outcome data using point of injury plasma are currently being explored in two large, actively enrolling US civilian trials: the Control of Major Bleeding After Trauma trial in Denver using a rapid, active, thawing of plasma in ambulances approved in 2014, and the PUPTH trial-Prehospital use of plasma in traumatic hemorrhage, which is partially funded by the US Department of Defense, also approved in 2014 (133, 134).
Other areas of important future research focus on identifying the specific plasma proteins involved in control or stabilization of the vascular endothelium. Identification of proteins involved in restoring tight junctions, rebuilding the glycocalyx, and inhibiting shedding of syndecan 1 would significantly impact current critical care protocols. Furthermore, identification of these specific proteins would improve the safety profile of plasma by focusing its therapeutic benefit and mitigating unnecessary product exposure.
The majority of plasma is currently obtained via single-donor preparation to limit infectious transmission (30). Ongoing research focuses on limiting transmission of plasma borne infections due to both present and emerging infectious etiologies (72). Additional research will determine whether blood group-specific plasma transfusions are necessary (33, 126). Future clinical trials will evaluate the efficacy of LP in addition to other, yet to be developed plasma formulations. Additional clinical research will focus on the effects of TEG-detected hypercoagulability on patient outcomes and location-dependent cytokine sampling effects on plasma cytokine levels (135, 136). Future animal studies will continue to investigate the optimal resuscitation volume for reconstitution, measure inflammatory markers in survival models using ascorbic acid or other buffers, and evaluate the efficacy of future-specific protein-derived formulations.
Balanced resuscitation of plasma:PRBC can improve survival, decrease total blood product requirements, limit iatrogenic crystalloids, and reduce complications in patients undergoing massive transfusions. Plasma is a complex solution containing many biologically active proteins with beneficial effects that extend well beyond correction of coagulopathy. LP increases the duration of safe storage, abrogates the need for refrigeration, and has proven efficacy in austere environments. Low volume reconstitution is effective, whereas the optimal fluid for reconstitution continues to be investigated.
We are now beginning to understand the possibility of creating a plasma-derived formulation that rapidly produces all of the associated benefits without the current logistical difficulties. In particular, some of the beneficial effects of plasma on the endothelium have been associated with specific proteins. This raises the future possibility that a small vial of plasma-derived proteins could result in rapid hemostasis, improved vascular stability, and tissue oxygenation while limiting third spacing, preventing organ failure, and improving survival at the point of injury.
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