key: cord-0042652-da9li8qb
authors: Lawless, Ryan A.; Holcomb, John B.
title: Plasma Transfusion
date: 2015-12-11
journal: Trauma Induced Coagulopathy
DOI: 10.1007/978-3-319-28308-1_20
sha: 9c4b79314f9ec0debe13938b13c514704143ea74
doc_id: 42652
cord_uid: da9li8qb

The resuscitation of the injured patient continues to be a highly debated topic. Multiple studies have been performed with the intent to determine the optimal strategy to combat, and ultimately prevent, trauma induced coagulopathy. This chapter discusses the risks and benefits of resuscitation protocols utilizing plasma. Plasma is the aqueous portion of blood that contains coagulation factors, fibrinolytic proteins, albumin, immunoglobulins, and up to 6000 other proteins. Multiple methods of collection and storage have been developed, each one affecting the plasma and its proteins differently. Once collected, plasma can be frozen for storage. If frozen within 8 h, the product is labelled as fresh frozen plasma (FFP). If frozen more than 6 h, but less than 24 h, it is labelled as plasma frozen within 24 h (FP24). When FFP and FP24 are mobilized from the blood bank, they are thawed in a water bath to create thawed plasma (TP) which can be stored in liquid form for up to 4 days prior to transfusion. Liquid plasma (LQP) is derived from whole blood and is never frozen. It can be stored for up to 30 days by some reports prior to transfusion. Each of these forms of plasma has been extensively studied for efficacy of coagulation and are all useful in the resuscitation of a traumatically injured patient. There is much more than coagulation factors in plasma that are useful to patients. Studies looking at the endotheliopathy associated with hemorrhagic shock have shown a decrease in the inflammatory response, promotion of endothelial repair, and decreased edema. Transfusion protocols utilizing plasma at the time of presentation have shown a decrease in the amount of blood products transfused, as well as an improvement in mortality. Transfusion ratios of platelets–red blood cells–plasma units in a 1:1:1 ratio have shown a significant improvement in mortality at 3 h post-admission over 1:1:2. There has not been an increase in the incidence of adverse events with the increase usage of plasma. The early administration of plasma to the massively hemorrhaging traumatically injured patient improves mortality, decreases total blood product usage, and promotes the resolution of trauma induced endotheliopathy without increasing adverse events.

There have been many advances in the management of patients suffering from traumatic injuries. However, trauma remains the leading cause of death in the civilian population younger than 44 years of age [ 1 ] . Uncontrolled hemorrhage , including non-compressible hemorrhage, accounts for approximately 40 % of traumarelated deaths [ 2 ] , in addition to 20-40 % of deaths following hospital admission [ 3 ] . As hemorrhage continues, patients develop hypovolemic shock in addition to tissue injuries that lead to the activation of multiple factors resulting in acute traumatic coagulopathy. Traumainduced coagulopathy in and of itself has been associated with an increase in mortality in the trauma population [ 4 -7 ] . Recently, Pati et al.

described the endotheliopathy of injury and used plasma to reverse or prevent this systemic injury altogether [ 8 ] . In this chapter, we discuss the role of plasma in the resuscitation of the traumatically injured patient to combat acute traumatic coagulopathy, but more importantly to prevent it all together.

In 2012, the Department of Health and Human Services published data from a survey collected in 2011 describing the utilization of blood and blood products across the USA. 5,926,000 units of plasma were produced for transfusion in total. This included 2,802,000 units of plasma frozen within 24 h (FP24), 1,813,000 units of fresh frozen plasma (FFP), 560,000 units of liquid plasma (LQP), and 251,000 units from apheresis collection. The overwhelming majority of units were collected and produced by blood centers with less than 10 % derived from hospitals. Additionally, 8, 195 ,000 units were produced for further manufacturing. In total, 3,882,000 units were transfused in 2011; a decrease of 13.4 % from 2008. The amount of FFP and FP24 transfused decreased over the 3-year period. However, the utilization of thawed plasma (TP) only became reportable in 2011. 1,181,000 units of TP were transfused, amounting to 30.4 % of all transfused plasma, and mostly being transfused at larger institutions. Finally, only 2000 units of LQP were transfused in 2011. The average cost of a unit of FFP and FP24 were $57.91 and $56.08 respectively [ 9 ] .

Plasma is the aqueous portion of blood that contains coagulation factors , fi brinolytic proteins, albumin, immunoglobulins, and up to 6000 individual proteins. It is derived from whole blood or apheresis collection. Once collected and produced it can be stored in the liquid state, frozen until needed for transfusion, or frozen then thawed and kept in the liquid state. The concentration of labile coagulation factors, namely factors V, VII, and VIII, are affected by the type of storage form plasma has undergone [ 10 ] .

In order to achieve the more balanced transfusion goal set forth by multiple military and civilian studies an immediate and plentiful supply of plasma is necessary. This becomes diffi cult in centers where thawed plasma is unavailable and in austere environments where cold chain storage and transportation is a limiting factor. As a result, much research and development has gone into the production and distribution of plasma products suitable for human transfusion. In this section we discuss the different plasma products available for transfusion. The characteristics of the different plasma preparations available for transfusion are summarized in Table 20 .1 .

Fresh frozen plasma is prepared either by separating the red blood cells and platelets from whole blood with centrifugation or by apheresis. The plasma is then frozen at −18 °C and stored until needed for transfusion. To be called FFP the freezing process must occur within 8 h of donor phlebotomy. FFP contains high levels of all coagulation factors including the labile factors V and VIII. Whole blood yields approximately 200-250 mL of FFP, where apheresis collection yields 400-600 mL. The components are diluted approximately 8-20 % by the anticoagulant, a mixture of citrate, phosphate buffer, and dextrose [ 10 -12 ] . Normal levels of factors V and VIII are found in FFP [ 10 ] . However, different blood groups yield different concentrations of coagulation factors confounding efforts to standardize therapy. The variations in expression can be as much as a 30 % difference between blood groups. This is exemplifi ed by blood group O level of factor VIII and von Willebrand factor being 30 % lower than other blood groups [ 11 , 12 ] .

FFP must be thawed in a water bath between 30 and 37 °C prior to transfusion, taking anywhere from 20 to 40 min. Furthermore, breakage of bags occurs in the water bath in approximately 10 % of cases, further delaying delivery to the bedside. The AABB also recommends against the utilization of FFP when a coagulopathy can be corrected by a more specifi c therapy, such as vitamin K, prothrombin complex, or specifi c coagulation factors. FFP is not the optimal therapy when complete reversal of warfarin is desired and should not be used in the absence of severe bleeding [ 13 ] .

Plasma collected via phlebotomy or apheresis and frozen between 8 and 24 h following collection becomes labelled as plasma frozen within 24 h (FP24). When derived from whole blood, a unit of FP24 yields a volume of 200-250 mL. However, an apheresis unit of FP24 yields 400-600 mL. FP24 contains high levels of stable coagulation factors and slightly diminished levels of the labile factors V, VIII, as well as Protein C due to the delayed in freezing from donor collection time [ 10 ] . , FP24 undergoes the same thawing process as FFP and also must be transfused within 24 h of returning to the liquid state [ 14 ] . If not transfused by that time, it can then be relabeled as thawed plasma [ 10 ] .

The indications and contraindications for FP24 utilization are identical to FFP (see section above). FP24 should not be used when the sole replacement of factors V and/or VIII is necessary [ 12 ] .

Thawed plasma (TP) is the liquid form of FFP or FP24 following a thaw at 30-37 °C. It is then stored at 1-6 °C to be used for up to 4 days following initial thaw. The levels of stable factors remain close to those of FFP and FP24 even at the 4-day point. However, there is a decline in the levels of labile factors, the most signifi cant of which being factor VIII [ 10 , 12 ] .

AABB indications for transfusion of TP include [ 10 , 12 , Thawed plasma is not recommended for the management of specifi c coagulation factor deficiencies as the concentration of the factors in the product is variable [ 10 ] .

Liquid plasma (LQP) is produced from whole blood no later than 5 days after expiration (21 days) and is never frozen [ 10 -12 , 14 ] . LQP is kept at 1-6 °C and can be stored for up to 30 days. The primary indication for transfusion of LQP is the management of the acutely hemorrhaging patient requiring massive transfusion. Studies have shown that the initial and prolonged hemostatic profi le of LQP, as determined by thromboelastography and calibrated thrombograms, is better than FFP or thawed plasma. Furthermore, the levels of coagulation factors remained ≥88 % of original levels out to 26 days, except for factors V and VIII [ 14 , 15 ] . As discussed, the vitamin K dependent factors (factors II, VII, IX, and X) are relatively stable under approved LQP storage conditions. Therefore, LQP is currently indicated in patients on warfarin therapy who are suffering massive hemorrhage. The labile factors (V and VIII) deplete over time during storage, making LQP less effective in patients with these specifi c defi ciencies [ 10 -12 ] .

The coagulation properties of LQP are superior to TP from FFP. Matijevic et al. analyzed the hemostatic potential of LQP as compared to TP derived from FFP. LQP had a superior capacity to form clot and generate thrombin. This phenomenon may be explained either by the presence of platelet microparticles in LQP not present in FFP, FP24, or TP, cold activation of coagulation proteins, the decline in protein S activity, or a combination thereof [ 14 ] . It is known that the freeze-thaw process required for FFP and FP24 degrades proteins; however, it is not understood why certain factors are less tolerant then others. By avoiding the freeze-thaw process the proteins remain functional longer to the point that 15-day-old LQP appears to function as well as 5-day-old TP [ 14 ] .

Currently, the goal of transfusion in the patient requiring massive transfusion is a balanced resuscitation with a ratio of platelets-plasma-red blood cells (RBC) units of 1:1:1 [ 16 -18 ] . Achieving this goal is often diffi cult in environments where a large and rapidly accessible supply of plasma is not available. As described previously, FFP and FP24 require frozen storage and re-warming under very controlled conditions. Furthermore, TP and LQP require storage under refrigerated (4 °C) conditions. This makes the rapid (within minutes of requirement) administration of plasma diffi cult at most civilian institutions and nearly impossible for military personnel. These factors, along with data indicating improved survival with balanced resuscitation, led to the recent redevelopment of dried human plasma. Lyophilization, a low-pressure, low-temperature, low-humidity process to convert plasma into powder, is not a new concept as it was fi rst developed and introduced into practice during World War II. Lyophilized plasma (LP) was widely used, and became the primary resuscitative fl uid on the battlefi eld by the end of WWII. Nevertheless, the concept was abandoned following unacceptable rates of viral transmission in the survivors, until modern screening methods improved transmission rates significantly [ 2 ] . LP possesses the same viscoelastic coagulation parameters as fresh plasma. In an animal model, Shuja et al. found an insignifi cant decrease in the activity of factors II, VII, and IX [ 19 ] . The French military has utilized dried plasma and has maintained a hemovigilance program since 1994. No adverse effects of infectious transmissions have been reported with the transfusion of more than 1100 units [ 20 ] . In 2011, Martinaud et al. described the utilization of freeze-dried plasma (FDP) in French intensive care units in Afghanistan, while caring for casualties from all the coalition forces [ 21 ] . The process of preparing the FDP involves the centrifugation of plasma. The supernatant is then removed and frozen by slow rotation in an ice slurry. The product is then freeze-dried at −8 °C for 48 h removing much of the CO 2 , resulting in an alkaline product upon rehydration [ 19 ] . FDP was described as easy to use, reconstituting in medical water within 10 min to provide 210 mL of fl uid with hemostatic and volume expansive properties. 236 units have been delivered and evaluated without a single adverse event reported [ 21 ] . Israeli Defense Forces (IDF) also utilizes FDP (from the German Red Cross) as the preferred resuscitation fl uid in the military prehospital setting. Using these dried products facilitates an environment of balanced transfusion from the point of initial resuscitation without playing "catch-up" while FFP thaws [ 22 ] .

To date, dried plasma products are not approved for use in the civilian population within the USA [ 23 , 24 ] . FDP from the French military has recently been approved by the Department of Defense, FDA and White House and is utilized by selected units of the US Special Forces. In addition to the French military and IDF, dried plasma products are utilized by the German and Norwegian militaries, Norwegian civilian emergency aeromedical services, and the US Army Special Operations Forces [ 22 ] . Further investigation for utilization in US civilian emergencies and ABO group universality are necessary as these products will allow plasma resuscitation to occur in environments not conducive to current plasma storage [ 23 -25 ] .

Spinella et al. recently performed a study on transfusion practices at Level I and II trauma centers using data from The American College of Surgeons (ACS) Trauma Quality Improvement Program (TQIP). These investigators report that he types of plasma used at these centers are as follows: 78 % thawed fresh frozen plasma/plasma frozen within 24 h, 16 % thawed fresh frozen plasma/plasma frozen within 24 h or liquid plasma , and 7 % (6 of 90) liquid plasma.

Patients in hemorrhagic shock suffer from a multitude of physiologic derangements. The early administration of blood products has been shown benefi cial throughout the literature. However, the reasoning behind plasma transfusion is not as simple as previously thought. Trauma patients lose blood; therefore, giving blood back makes sense. However, reaching for packed RBCs fi rst does not accomplish the goal which the trauma community is trying to achieve: restoration of circulating volume. The transfusion of plasma will restore circulating blood volume while delivering coagulation factors to bleeding patients actively consuming coagulation factors. Early administration of plasma, in the prehospital setting, as well as in the emergency center, has been shown to improve acid-base status upon admission, decrease the total transfusion requirement in the fi rst 24 h following admission, and reducing mortality risk [ 25 -27 ] .

A decade ago, military and civilian physicians transfused plasma in order to correct coagulopathy. With increasing clinical experience on earlier and balanced use of plasma, the prevention of trauma-induced coagulopathy and endothelial dysfunction became the intent for transfusion based upon laboratory-based measures of coagulopathy. With increasing research and understanding as to the endothelial injury associated with massive trauma, treating the endotheliopathy of trauma has also become a goal for plasma transfusion [ 28 ] . This evolution of thought has been derived from a greater understanding of how hemorrhagic shock systemically affects physiology. Restoration of circulating coagulation factors is not the sole purpose for transfusion of plasma in patients with hemorrhagic shock.

The endotheliopathy of trauma (injury) refers to the breakdown of the endothelial glycocalyx on the endoluminal surface of blood vessels increasing permeability and decreasing their integrity. It has been hypothesized that injury to the endothelial glycocalyx leads to interstitial edema, infl ammation, and tissue hypoxia [ 29 , 30 ] . For further description of the endotheliopathy of trauma please refer to Chap. 7 . At the Texas Trauma Institute we have anecdotally observed a decrease in edema, as well as a paucity of abdominal compartment syndrome secondary to resuscitation with the initiation of blood product based resuscitation. Animal data suggests a decrease in infl ammation with transfusion of plasma when compared to infusion of albumin, artifi cial colloid, and crystalloid in a hemorrhage shock model [ 31 -35 ] .

Projecting from the endoluminal surface of blood vessels is a complex network of soluble components creating an endothelial glycocalyx.

Multiple proteoglycans and glycoprotein comprise this network providing surfaces for interactions with glycosaminoglycans, neutrophil-endothelial cell interactions that occur with injury to the glycocalyx, hemostasis, coagulation, and fi brinolysis. The glycocalyx allows the plasma component of blood to interact with the vessel wall while maintaining a barrier to erythrocytes and leukocytes [ 31 -33 ] . Kozar et al. demonstrated that the endothelial glycocalyx is injured during hemorrhagic shock, manifested by shedding into plasma of syndecan-1, one of the endothelial glycocalyx's proteoglycans [ 36 ] . This had been previously demonstrated in models of ischemia and reperfusion. Furthermore, these authors demonstrated that the injured glycocalyx is partially repaired with the transfusion of plasma in comparison to the infusion of crystalloid solution [ 36 -38 ] . In their study, significantly less volume was needed in the plasma group to maintain mean arterial pressure. The intact glycocalyx was ablated by hemorrhagic shock and signs of early restoration of the glycocalyx were present in the plasma group in comparison to the crystalloid group. Shown in Fig. 20 .1 are electron microscopy images of mesenteric venules showing the effects of shock and resuscitation on the endothelial glycocalyx along with its thickness. Furthermore, the authors investigated lung injury with respect to hemorrhagic shock based on alveolar thickness, capillary congestion, and cellularity. They found an increase in all three parameters in the shock model compared to sham. However, the infusion of crystalloid increased all three parameters above the model, while the plasma transfusion group had improvement of all three parameters, suggesting attenuation of lung injury [ 36 ] . These fi ndings were also demonstrated by Pati et al.; however, they also demonstrated that the age of Fig. 20.1 Electron microscopy of mesenteric venules stained to reveal endothelial glycocalyx following hemorrhagic insult and resuscitation the plasma transfused also had an effect on this attenuation of lung injury (older plasma being less benefi cial) [ 8 ] . Nevertheless, day 5 plasma stored at 4 °C remained superior to crystalloid infusion with respect to reparative capacity in the animal model [ 8 ] . This indicates that a component of plasma, in soluble form, interacts with the endothelial membrane to restore the endothelial glycocalyx. Figure 20 .2 shows the vascular injury caused by hemorrhagic shock through hypoxia leading to cell contraction and decreased vascular permeability. Resuscitation with plasma decreases the infl ammatory response, promotes endothelial repair, and leads to normalization of the endothelium. This leads to a decrease in vascular permeability; clinically seen as less edema.

In 2011, Haywood-Watson et al. found that patients arriving to a level 1 trauma center in hemorrhagic shock had an elevated level of the endothelial proteoglycan syndecan-1 [ 39 ] .

The shedding of syndecan-1 was negatively correlated with pro-infl ammatory cytokines INF-gamma, fractalkine, and IL-1beta, and positively correlated with IL-10, an anti-infl ammatory cytokine [ 39 ] . This correlation suggests that syndecan-1 is not just a marker of endotheliopathy; it may be involved in the restoration of glycocalyx integrity as depicted in Fig. 20 .3 [ 39 ] . Furthermore, Johansson et al. found an elevated admission syndecan-1 level in severely injured trauma patients to be associated with infl ammation, coagulopathy, and increased mortality [ 40 ] .

The institution of exsanguination protocols at major trauma centers has been shown to improve survival [ 41 , 42 ] . The original investigation did not specifi cally involve a balanced ratio resuscitation. Simply by initiating a protocol for the delivery of blood products to the emergency center for an exsanguinating patient, mortality improved. The activation of a " massive trauma protocol" delivered blood component therapy to the emergency center without the request of specifi c components by the trauma team. This was also demonstrated in the military environment with improved survival in both Iraq and Afghanistan [ 43 , 44 ] . Furthermore, a decrease in the total amount of blood products transfused was seen [ 41 , 42 , 45 , 46 ] .

The majority of trauma centers store uncrossmatched RBCs in the emergency center. However, plasma often remains in the blood bank awaiting the activation of the massive transfusion protocol or a direct order from a physician. The lack of readily available plasma makes it diffi cult to achieve a high plasma-RBC ratio in an expedited fashion, which has been shown in multiple studies to decrease mortality [ 47 , 48 ] . By implementing an emergency center thawed plasma protocol, with 4 units of thawed AB plasma stored in the emergency center, the time to first plasma transfusion was improved by 46 min resulting in a decrease in 24-h transfusion of PRBCs, plasma, and platelets and a signifi cant decrease in mortality [ 27 ] . Furthermore, a decrease in the rate of the activation of the massive transfusion protocol was seen following the implementation of the thawed plasma in the emergency center [ 27 ] , as well as with attaining increased plasma-RBC ratios [ 49 ] .

The Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study demonstrated that earlier transfusion of plasma, within minutes of identifi cation of hemorrhagic shock, and achieving high early plasma-RBC ratios decreased 24-h and 30-day mortality. This was evidenced by the three-to fourfold increased mortality risk associated with plasma-RBC ratios <1:2 [ 17 , 28 , 50 ] . Furthermore, gradual achievement of balanced transfusion ratios may not be as benefi cial as early plasma transfusion [ 50 ] . Initiating plasma transfusion early also led to a decrease in the total amount of RBCs transfused during the initial 24 h following admission [ 50 ] . PROMMTT clearly showed that earlier plasma was associated with improved survival; however, few patients received consistent ratios. There was signifi cant concern that higher ratios would lead to increased hypoxia, acute respiratory distress syndrome (ARDS) and transfusion related acute lung injury (TRALI) . However, Robinson et al. showed that hypoxia was associated with excessive crystalloid infusion rather than plasma [ 51 ] . Lastly, it was clear from the PROMMTT data that the two ratios that clinicians were trying to transfuse were 1:1 and 1:2.

The PROMMTT study was followed by the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) study which evaluated the effectiveness and safety of two transfusion strategies in patients with major trauma and severe bleeding. The PROPPR study was the fi rst multicenter randomized trial comparing transfusion strategies with mortality as the primary endpoint. It provided evidence for the commonly held belief that balanced transfusion protocols were benefi cial to severely injured patients with hemorrhagic shock. Although no signifi cant differences in 24-h and 30-day mortality were found between the two transfusion ratios investigated (plasma-platelet-RBC ratio of 1:1:1 versus 1:1:2), the early availability of blood products transfused within minutes of arrival in a balanced (1:1:1) ratio achieved hemostasis more often and decreased hemorrhage-related deaths within the fi rst 24 h following admission [ 18 ] . Furthermore, while the balanced transfusion group received signifi cantly more plasma and platelets within the fi rst 24 h, no difference was found in the rate of 23 prespecifi ed complications including the systemic infl ammatory response syndrome (SIRS), ARDS, transfusion associated circulatory overload (TACO), TRALI, and allergic reactions. Consistent with the biology of bleeding patients, the median time to hemorrhagic death in PROPPR was 2.3 h. In a post hoc analysis, at 3 h after admission there was a signifi cant mortality difference between the two groups [ 18 ] .

The concept used at the Texas Trauma Institute at Memorial Hermann Hospital in Houston has been derived from the experiences gained on the battlefi eld, and supported by military and civilian studies. In the prehospital setting the emphasis centers on the cessation of bleeding. This occurs in parallel with hypotensive resuscitation utilizing liquid plasma and packed red blood cells. LQP and packed RBCs are utilized by our hospital-based helicopter program, Life Flight. Patients are identifi ed as requiring a prehospital transfusion based upon the assessment of blood consumption (ABC) score. Over a 20-month study period, 942 units (244 RBCs and 698 plasma units) were placed on the Life Flight helicopters with a 1.9 % waste rate [ 26 ] . Once a severely injured patient reaches the trauma center, a rapid thromboelastograph (r-TEG), venous blood gas, and hemoglobin levels are drawn and immediately analyzed. In patients that have an ABC score <2 (1 point each for penetrating mechanism, systolic blood pressure <90 mmHg, heart rate >120 beats/min, and a positive focused abdominal assessment with sonography for trauma) or without substantial bleeding (<3 units/h), the r-TEG is used to guide blood product resuscitation [ 52 ] . Patients that are in shock, are hypotensive, or have an ABC score ≥ 2 are started on the massive transfusion protocol and receive 1:1:1 ratio-driven resuscitation [ 53 ] . The patient then either proceeds to the operating room or interventional radiology. The response to resuscitation is closely monitored. Once clinical bleeding has slowed considerably or ceased the resuscitation is converted to goaldriven resuscitation utilizing r-TEG [ 53 ] .

Of all transfusable blood products, plasma, specifi cally FFP, is considered the most hazardous according to multiple studies into the mid-2000s. However, the overall risk remains low. The major risks include TRALI, TACO, infectious disease transmissions, acute transfusion reactions, and leukocyte-associated reactions. However, most of these studies only evaluated some of the blood products that are infused, frequently not evaluating the effects of RBCs, platelets or crystalloids, all which have well described deleterious effects.

Transfusion related acute lung injury manifests as hypoxia, pulmonary edema, pulmonary infi ltrates with radiographic changes, fevers, and possibly hypotension within 6 h of plasma transfusion. The presentation is similar to ARDS; however, >80 % of patients typically recover within a few days of symptom onset and treatment is mainly supportive [ 54 -56 ] .

The UK hemovigilance Serious Hazards of Transfusion (SHOT) reports a TRALI risk of 1 in 63,940 transfused units, a 28.8 % decrease since 2008 [ 9 , 57 ] . It is the most common cause of death from transfusion and is the most frequent serious complication of FFP transfusion [ 58 ] . In 2013, the FDA reported that TRALI represented 37 % of all fatalities secondary to blood transfusions for that year and 38 % from 2009 to 2013. Plasma, specifi cally FP24 was implicated in two of the 17 cases and a plasma product may have been implicated in four other cases that received multiple transfusions. Interestingly, no units of FFP were implicated in 2013. The number of cases of TRALI has signifi cantly decreased over the study period following voluntary measures taken by the transfusion community [ 59 ] . The absolute numbers of TRALI are very low, a testament to the rigorous testing performed by the blood banking community.

TRALI is signifi cantly associated with leukocyte alloantibodies found in the donor plasma. These specifi c antibodies are found exclusively in post-partum female plasma and in male plasma from donors who have previous received a transfusion. Some authors believe TRALI to develop in two steps. A predisposing condition must be present that incites the release of cytokines leading to the attachment of neutrophils to the pulmonary capillary endothelium. The second step occurs with neutrophil priming, activation and pulmonary injury [ 13 , 60 ] . In 2008, Eder et al. reported a reduction in the incidence of TRALI with the conversion to male-predominant plasma for transfusion [ 13 , 61 ] . Unpublished data from the Texas Trauma Institute demonstrate that with the increase usage of plasma in resuscitating trauma patients the incidence of TRALI did not increase. There were nine incidences of TRALI related to plasma transfusion in over 180,000 units transfused. The incidence was approximately 1:20,000 units [ 62 ] .

Further discussion amongst hemovigilance programs regarding standardization of the defi nition of TRALI versus TACO will improve the way health care workers identify and manage transfusion reactions [ 63 , 64 ] .

Transfusion associated circulatory overload occurs secondary to increased hydrostatic pressure resulting in pulmonary edema. This process can be indistinguishable from TRALI and the two entities may in fact co-exist [ 64 ] . In 2013, the FDA reported that TACO represented 34 % of transfusion related mortalities for that year. There has been an uptrend in mortality related to TACO over time. It is diffi cult to determine whether the uptrend is secondary to improved diagnostics or actual increase in incidence [ 59 ] .

The incidence of TACO is not well described in the literature. Multiple retrospective reviews have reported an incidence of TACO from <1 % to 11 % [ 55 , 64 ] . This range with multiple reports is secondary to the diffi culty in determining the etiology of pulmonary edema as diagnostic evaluations for TACO are invasive and serologic tests for TRALI have yet to be validated. In Fig. 20 .4 , Gajic et al. designed an algorithm to determine the etiology of post-transfusion acute pulmonary edema [ 64 ] . The algorithm is based on the European-American ARDS Consensus Conference defi nitions of TRALI and integrates specifi c laboratory values into the decision-making process. Frequently, TACO is a post-hoc diagnosis made once a patient responds to a specifi c therapy [ 55 ] .

The transmission of infectious diseases has dramatically decreased with extensive donor screening and infectious disease testing. Nucleic acid testing sensitivity has improved leading to a decrease in transmission risk. This has led to an estimated risk of 1:1,467,000 for acquiring HIV, 1:1,149,000 for hepatitis C virus, and 1:280,000 donations for hepatitis B virus [ 58 , 65 , 66 ] .

Outside the USA, many blood centers utilize donor retested plasma, pathogen inactivated plasma, and pathogen reduced plasma [ 67 ] . Donor retested plasma are units that are quarantined until the donor submits a subsequent donation which tests negative for infectious disease [ 67 ] . Pathogen inactivated and pathogen reduced plasma are prepared via the addition of chemicals (solvent/detergent, methylene blue, amotosalen, ribofl avin, and UV light) to prevent the transmission of lipid-enveloped viruses [ 68 , 69 ] . Two companies leading this technology are Terumo Medical Corp. (Somerset, NJ) and Cerus Europe B.V. (Amersfoort, NL). The Cerus process was FDA approved in early 2015.

The freezing process during preparation of plasma inactivates bacteria. Furthermore, bacterial contamination with the production of endotoxin prior to freezing is unlikely [ 58 ] . The 2013 FDA report describes a single bacterial infection transmitted through plasma transfusion [ 59 ] . The process of removing cellular components via fi lters also removes cell-associated bacteria, most protozoa, and cell-associated viruses including malaria, CMV, and HTLV. Freezing does not remove the free viruses including Hepatitis A, B, and C, HIV 1 and 2, and parvovirus B19 [ 13 , 58 ] .

Currently, no screening protocol exists for the detection of prion diseases. Furthermore, modern techniques of decreasing infectious transmission are ineffective against prion diseases. In the UK, three possible cases of variant Creutzfeldt-Jakob disease (vCJD) have been reported. Each case involved transfusion of non-leukocyte reduced red blood cells [ 70 ] . There have been no reported cases of prion disease transmission following plasma transfusion; however, animal studies have shown that it is possible [ 71 ] .

In 2013, the 17th Annual SHOT Report described just over 3000 acute transfusion reactions in over 13,000 transfusions. Three hundred and twenty incidents occurred in 2012 including allergic, hypotensive, and severe febrile reactions. Thirtyone cases were associated with transfusion of FFP, which included 13 anaphylactic/severe allergic reactions, 12 moderate allergic reactions, four hypotensive reactions, one febrile reaction, and one mixed febrile/allergic reaction. No deaths were related to any type of transfusion reaction [ 57 ] . Moderate allergic reactions present with an urticarial rash, wheezing, and other symptoms not severe enough to be termed anaphylactic and occur in 1-3 % of transfusions. Anaphylaxis includes bronchospasm, angioedema, severe hypotension, and cardiovascular collapse and is a rare occurrence [ 13 , 55 , 57 , 58 , 68 ] . Other than human immunoglobulin A (IgA) and haptoglobin, the proteins involved in acute transfusion reactions are unknown and generally unpredictable. For patients known to have an IgA sensitivity, plasma obtained from patient with IgA defi ciency is available for transfusion [ 13 , 72 ] .

Leukocyte-associated reactions following plasma transfusion are rare. The freeze-thaw process yields a small percentage of viable leukocytes prior to transfusion [ 73 , 74 ] . The presence of viable leukocytes leads to the rare occurrence of febrile non-hemolytic transfusion reactions (FNHTR), transfusion-associated graft versus host disease (TA-GVHD), and transmission of leukocyte viruses [ 68 ] .

Following the freeze-thaw process nonviable leukocytes release mediators that may contribute to FNHTRs. These reactions are generally clinically insignifi cant and resolve quickly with supportive therapy [ 57 , 68 ] .

TA-GVHD requires viable leukocytes to be transfused and then engraft and proliferate in the host patient. This is a rare transfusion reaction amongst all blood components transfused and has yet to be reported with FFP transfusion. Therefore, irradiation of FFP is not currently recommended [ 68 ] .

The utilization of plasma as the primary resuscitation fl uid has been the subject of multiple retrospective studies, a large prospective observational study and a recent prospective randomized trial. The benefi ts of balanced transfusion with respect to hemorrhagic mortality in the trauma population have been reported. Current randomized studies are evaluating the utility of plasma in the prehospital area. Future investigations will likely include the utilization of dried plasma products in the US civilian population with the longer storage life and substantial logistic benefi ts.

Increasing trauma deaths in the United States

The use of lyophilized plasma in a severe multi-injury pig model

Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the resuscitation outcomes consortium

Predictors of mortality in trauma patients

Acute traumatic coagulopathy

Early coagulopathy predicts mortality in trauma

Increased mortality associated with the early coagulopathy of trauma in combat casualties

Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw

Report of the US Department of Health and Human Services. The 2011 National Blood Collection and Utilization Survey Report

Circular of information for the use of human blood and blood components

Coagulation profi le of liquid-state plasma

Plasma components: properties, differences, and uses

Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant

Better hemostatic profi les of never-frozen liquid plasma compared with thawed fresh frozen plasma

Never-frozen liquid plasma blocks endothelial permeability as effectively as thawed fresh frozen plasma

The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a Combat Support Hospital

The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks

Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial

Development and testing of freezedried plasma for the treatment of trauma-associated coagulopathy

The evolving role of lyophilized plasma in remote damage control resuscitation in the French Armed Forces Health Service

Use of freeze-dried plasma in French Intensive Care Unit in Afghanistan

Freeze-dried plasma at the point of injury: from concept to doctrine

Freeze-dried plasma

Advances in military, fi eld, and austere transfusion medicine in the last decade

Freeze dried plasma: a French army specialty

Prehospital transfusion of plasma and red blood cells in trauma patients

An emergency department thawed plasma protocol for severely injured patients

Optimal trauma resuscitation with plasma as the primary resuscitative fl uid: the surgeon's perspective

A new target for tumor therapy

In vivo evaluation of venular glycocalyx during hemorrhagic shock in rats using intravital microscopy

Effect of different resuscitation strategies on neutrophil activation in a swine model of hemorrhagic shock

Lactated ringer's solution and hetastarch but not plasma resuscitation after rat hemorrhagic shock is associated with immediate lung apoptosis by the upregulation of Bax protein

Endothelial glycocalyx as an additional barrier determining extravasation of 6% hydroxyethyl starch or 5% albumin solutions in the coronary vascular bed

Fresh frozen plasma lessens pulmonary endothelial infl ammation and hyperpermeability after hemorrhagic shock and is associated with loss of sydecan-1

Evaluation of resuscitation fl uids on endothelial glycocalyx, venular blood fl ow, and coagulation function after hemorrhagic shock in rats

Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock

The endothelial surface layer. Pfl ugers Arch Eur

Blood fl ow resistance during hemodilution: effect of plasma composition

Modulation of syndecan-1 shedding after hemorrhagic shock and resuscitation

A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with infl ammation, protein C depletion, fi brinolysis, and increased mortality in trauma patients

Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization

Massive transfusion protocols: the role of aggressive resuscitation versus product ratio in mortality reduction

Ten-year analysis of transfusion in Operation Iraqi Freedom and Operation Enduring Freedom: increased plasma and platelet use correlates with improved survival

Damage control resuscitation: directly addressing the early coagulopathy of trauma

A massive transfusion protocol to decrease blood component use and costs

An FFP:PRBC transfusion ratio ≥1:1.5 is associated with a lower risk of mortality after massive transfusion

Room for (performance) improvement: provider-related factors associated with poor outcomes in massive transfusion

Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients

Changes in massive transfusion over time: an early shift in the right direction?

Resuscitate early with plasma and platelets or balanced blood products gradually: fi ndings from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study

Application of the Berlin defi nition in PROMMTT patients: the impact of resuscitation on the incidence of hypoxemia

Early prediction of massive transfusion in trauma: simple as ABC (assessment of blood consumption

How I treat patients with massive hemorrhage

Transfusion-related acute lung injury: defi nition and review

Reducing noninfectious risks of blood transfusion

Transfusion related acute lung injury as neglected, serious complication of haemotherapy

Risks of fresh frozen plasma and platelets

Fatalities reported to FDA following blood collection and transfusion: annual summary for fi scal year 2013

The two-event model of transfusionrelated acute lung injury

Effective reduction of transfusion-related acute lung injury risk with malepredominant plasma strategy in the American Red Cross

The incidence of transfusion-related acute lung injury (TRALI) at a large, tertiary medical center: a decade's experience. Presented at the Thrombosis and Hemostasis Summit of North America

Cumulative risks of early fresh frozen plasma, cryoprecipitate and platelet transfusion in Europe

Pulmonary edema after transfusion: how to differentiate transfusion-associated circulatory overload from transfusion-related acute lung injury

Prevalence, incidence, and residual risk of human immunodefi ciency virus and hepatitis C infections among United States blood donors since the introduction of nucleic acid testing

Current incidence and residual risk of hepatitis B infection among blood donors in the United States

Completely converting a blood service region to the use of safer plasma

Adverse effects of plasma transfusion

The use of solvent/detergent treatment in pathogen reduction of plasma

Creutfeld-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review Study

The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy

How I manage patients suspected of having an IgA anaphylactic transfusion reaction

Effect of leucocyte reduction on the potential alloimmunogenicity of leucocytes in freshfrozen plasma products

White cells in fresh-frozen plasma: evaluation of a new white cell-reduction fi lter