Because of the nature of frozen plasma, transfusion delays of 45 min occur as units are thawed and prepared. Young and colleagues surveyed members of the University Health System Consortium, consisting of 107 academic medical centers and 232 affiliated hospitals and found that only 60% of participating hospitals had thawed plasma sufficient for the first cycle of their MTP. This problem delays the critical availability of plasma in the initial phase of resuscitation. Reviews of plasma, cryoprecipitate and platelet transfusions alongside massive blood transfusion protocols have demonstrated that earlier use of plasma and platelets in trauma patients have decreased the incidence of coagulopathy [21]. Unfortunately, by the time one or more blood volumes have been lost, plasma may still be unavailable in the absence of a thawed or liquid plasma program. Hence, protocols have been established to reduce wastage of products and use them for patients in an efficacious manner [22].

Red blood cells are the component of choice used to restore hemoglobin levels in resuscitation. More than 30% of intensive care unit (ICU) patients receive RBC transfusions and more than 40% are transfused during hospitalization [23]. The Cardiovascular Health Study found that anemia is associated with increased mortality in elderly patients, emphasizing the importance of treatment [24]. However, correction of anemia in surgical patients has not been readily studied, and its benefits remain controversial.

In their review, Englesbe et al. note that there is not yet a consensus of in what degree of anemia can RBC transfusions offer a benefit [25]. They discuss the current findings by various studies, which have found that survival was not increased when postoperative patients were transfused to correct a hematocrit of 25%, and similarly, while studies favor transfusion in cardiac patients with a hematocrit of 33% or less, a true benefit remains to be seen. Hence, they recommend making the decision to transfuse using a host of physiological measures and evaluation of the patient’s compensatory ability, not only the hematocrit. They have used a trigger of a hematocrit of 16% for initiating transfusion when the patient has excellent compensatory ability, and 21% when this is not the case [25]. The 21% trigger should also be employed in stable elderly patients without tachycardia or hypoxia. Otherwise, their investigations have not yet shown benefits in stratification of surgical patients by specialty or procedures. One surgical population that has been studied with regards to transfusion is patients undergoing infrarenal abdominal aortic aneurysm surgery. A meta-analysis of randomized controlled trials demonstrated that intraoperative autotransfusion in these patients decreased the allogeneic blood transfusion requirement [26].

High quality evidence, notably Hébert et al.’s, exists to support conservative triggers for RBC transfusion in critically ill patients [27]. This multicenter randomized, controlled, clinical trial of 838 critically ill patients compared the outcomes of patients who were transfused at hemoglobin levels of less than 7.0 g/dL and those who were transfused at hemoglobin levels below 10.0 g/dL. Their study ultimately found that the more restrictive trigger of 7.0 g/dL was superior to the liberal one and patients experienced improved 30-day survival rates. Of note, of the various patient populations studied, this improvement was not found to be significant in patients with acute myocardial infarction and unstable angina [27].

It is important to be mindful of false triggers for transfusion, such as anemia due to hemodilution, commonly seen in patients receiving fluids during prolonged hospital stays. A peripheral hematocrit is not enough to determine the patient’s red blood cell levels, and calculations of total blood volume, red blood cell volumes, and normalized hematocrit are necessary [28]. Van et al. report that relying on peripheral hematocrit alone resulted in overdiagnosis of anemia in 23.8% of analyses, and this finding can lead to unnecessary transfusions. Blood Volume Analyzers are one option that has been shown to separate anemia due to hemodilution compared to other sources such as surgical bleeding [28].

In patients with prolonged hospital stays and critically ill patients, it is important to keep in mind anemia due to phlebotomy for various laboratory testing and other needs [23]. Between 40 and 240 ml of blood per day is collected from ICU patients, with surgical patients generally on the higher end. Hence, the conservation of blood and reducing unnecessary blood draws is key to preventing a need for pRBC transfusions.

Plasma is an acellular blood product consisting of clotting factors involved in coagulation and fibrinolysis, as well as proteins involved in immune reactions and maintenance the oncotic balance of blood. Plasma can be obtained from separation of whole blood or unique plasma donations from a donor using plasmapheresis. Common indications for plasma are reversal of warfarin-induced anticoagulation, massive transfusion in trauma and surgery, procedures with limited bleeding or risk thereof, liver disease with coagulation factor deficiencies, single coagulation factor deficiency, and thrombotic thrombocytopenic purpura (TTP) [34].

Historically, plasma transfusions have been associated with various side effects including transfusion related acute lung injury (TRALI) [35]. However, these complications have been dramatically reduced with blood donation centers transitioning to male only and/or nulliparous female donors [36].

Norda et al. studied two types of plasma: thawed plasma and liquid plasma (never frozen). Liquid plasma is an AABB approved product and may be stored at 2–6°C for up to 26 days. Both of these types of plasma have been considered clinically equivalent. As for their individual components, liquid plasma has been shown to contain levels of Factor V and von Willebrand factor at levels 70% or greater. However, studies have noted that C1 esterase inhibitor (C1INH) was consumed by day 14 in 22% of plasma products due to cold-induced contact activation [37]. In order to avoid this effect that places patients at risk for inadequate perfusion, some institutions have introduced a maximum storage time of 7 days for nonfrozen plasma [37].

Murad et al.’s meta-analysis of 37 studies on adults transfused with plasma compared with nontransfused controls demonstrated that in the setting of massive transfusions in trauma patients, transfusion may be associated with increased survival and decreased multiorgan failure. However, they also noted increased mortality in patients who received plasma not part of a massive transfusion protocol. This finding may be due to the unbalanced ratio of transfusion of products, unlike in mass transfusion protocols, which call for 1:1 transfusion of RBCs and plasma. In addition, plasma transfusion was associated with increased risk of developing TRALI, and by itself did not reduce transfusion requirements [34]. Their findings, in the first comprehensive meta-analysis and systematic review of plasma transfusion outcomes, highlight the need of assessing each patient’s indications for plasma. The maturation of this field will be needed to strengthen the findings, which the authors did note were subject to survivor biases in some studies. However, none of these studies involved the use of plasma in patients with hemorrhagic shock. In this population of patients, the incidence of multi-organ failure has been shown to be lower than comparison cohorts (most likely as a result of less overall transfusions in the higher plasma group) [13, 14].

The purpose of platelet transfusions is to avoid spontaneous hemorrhage, which can occur at very low platelet levels, especially in patients who are already hemorrhaging or have various platelet deficiencies and abnormalities of function. Along with plasma and fibrinogen, platelets are key in achieving hemostasis in the obstetric patient with post-partum hemorrhage [38]. Approximately 50,000 cells/L of platelets are necessary in order to achieve adequate hemostasis. In addition to the total number of platelets, their quality is also important to overall hemostatic function. A patient’s platelets must be efficacious, that is, remaining in circulation and completing its physiological role in clot formation [39]. This efficacy can be assessed by various modalities, from the traditional laboratory coagulation studies to the more recent thrombelastograms (TEG), also known as thromboelastography, and this topic is covered in the last section.

Cryoprecipitate consists of von Willebrand factor/VIII complex, factor XIII, and fibrinogen. It is used to supplement plasma transfusions with fibrinogen, especially in patients with fibrinogen levels of less than 100 mg/dL, the level at which hypofibrinogenemia results in bleeding [5]. It is named cryoprecipitate because single units of plasma are rapidly frozen to −30°C and are slowly thawed overnight to 4°C, causing many clotting factors such as fibrinogen to precipitate out of the solution [35]. Indications for cryoprecipitate include factor VII deficiency, congenital or acquired hypofibrinogenemia, disseminated intravascular coagulation, and massive transfusion.

Unlike plasma, virus-inactivated cryoprecipitate is not yet available, and studies on the efficacy of SD FFP and MB FFP have not shown a benefit [35]. The complications of cryoprecipitate are similar to those of plasma, with a slightly lower occurrence of complications associated with higher volumes of plasma, such as TRALI and hemolysis [35].

The practice of using whole blood is largely uncommon due to the separation of blood components for targeting specific deficiencies currently supported by evidence-based medicine. Decision-making for each transfusion requires laboratory testing, and each product must carefully be stored and transported to the site of need. When this is not possible, such as in acute settings with limited resources, whole blood transfusions can adequately resuscitate certain patients. Grosso et al. recount a case of collecting whole blood from hospital personnel donors in a US field surgical hospital in Kosovo [40]. This whole blood was used to treat exsanguinating coagulopathy in an acutely bleeding patient. The advantage of whole blood is its ability to increase hemoglobin levels, similarly to red blood cells, and its ability to restore blood volumes, similarly to crystalloids [40]. Because of its physiological ratios of each blood component, it may hold an advantage over individual blood component transfusions, but more work is necessary to substantiate this idea.

Recombinant activated factor VII (rFVIIa), originally developed for use in hemophilia A and B patients, has recently been explored in various off-label uses, such as stemming acute bleeding alongside standard replacement therapy. Mayo et al. demonstrate the use of a coagulopathy score that they found to be statistically correlated to rFVIIa response and survival in 13 trauma patients in Israel [41]. This finding was a turning point in the understanding of rFVIIa indications due to its previous contraindication in coagulopathy. Other uses for rFVIIa are factor VII deficiency, thrombocytopenia, functional platelet disorders, von Willebrand disease, intracranial bleeding, and reversal of warfarin overdose, liver disease, and transplantation. However, little evidence is currently available to support these uses [41].

Before entering the discussion on complications related to transfusions, the difficulty of study design to answer such questions must be appreciated. There are ethical obstacles to randomizing patients to transfusion and non-transfusion arms. Hence, many trials show patients who received more blood component transfusions fared worse than patients who did not, but this may be entirely because of the condition of the patients that necessitated the transfusions [25]. Khorana et al.’s retrospective cohort study of 504,208 patients hospitalized with cancer demonstrated that RBC and platelet transfusions were associated with increased mortality, as well as venous and arterial thrombotic events [42]. However, it is unclear if this is a causal relationship.

As with large-scale introduction of exogenous elements to the body, immune reactions can develop, a sequela that is notorious in blood products. This complication is particularly devastating in severely ill patients. The most notorious of these immune reactions are hemolytic reactions. In order to prevent this event, it is important to cross-match patient and donor blood whenever possible. The most common cause of hemolytic reactions due to transfusion of an incorrect match is clerical error. Hemolytic reactions in blood transfusions occur because each individual carries antibodies against the blood group (A or B) that it does not express endogenously. Hence, when products containing anti-A or anti-B antibodies in plasma, such as plasma, are transfused to patients of A, B, or both blood groups, the donor antibodies stage an attack on the patient’s red blood cells. Allergic reactions are another common immune-mediated complication of transfusions. Severely anaphylactic reactions are more common after plasma compared to RBC transfusion [35]. Patients present with wheeze, hypotension, tachycardia, laryngeal edema, and urticarial rash.

TRALI is defined as acute lung injury occurring within 6 h of transfusion with a blood product, with most commonly reported cases occurring due to FFP [43]. TRALI is the most common cause of death due to transfusion [35]. TRALI is characterized by respiratory insufficiency, not limited to but including tachypnea, cyanosis, dyspnea, and acute hypoxemia [43]. Unfortunately, the occurrence of TRALI in critically ill patients who received a blood transfusion is estimated to be around 25% and increases with each subsequent transfusion, has a mortality rate of approximately 40%, and it is the most common transfusion-related complication [16]. Eighty-five percent of patients with bleeding varices receive blood transfusions, and the trigger for transfusions is much debated. In patients with gastrointestinal bleeding, TRALI is further exacerbated by the presence of end-stage liver disease. Proposed mechanisms for this phenomenon have included antibody-mediated reactions, but these findings are not definitive and many are subject to selection bias due to no screening in the asymptomatic population [43]. Autopsies and animal models have suggested hyperactive PMN involvement, since mass infiltration was noted [43]. A two-event model has also been proposed, with the first event dictated by the clinical health of the patient and the second event by the quality (affected by storage, donor immunologic components) of the blood product [43]. The treatment of TRALI is aggressive respiratory support and ventilation in more severe cases, such as in critically ill patients [43]. Practices to reduce the risk of TRALI include prestorage leukoreduction as well as avoiding the use of old blood products, defined as older than 14 days for RBCs and older than 2 days for platelet concentrates. Another prevention strategy is using only male donors or donors who have never been pregnant due to look back studies showing fewer TRALI events in blood donations from those populations [16]. Eder et al. demonstrated that preferential distribution of plasma from male donors reduced the reported number of TRALI cases [44].

Transfusion-associated immunomodulation refers to the immunosuppression resulting from the introduction of foreign antigens via blood products to the host [25]. The exact mechanism of this effect has not yet been elucidated, but plasma components, white blood cells (WBCs), metabolic products from storage processes are thought to play a role. This effect may be responsible for the immunosuppressive effects of transfusions on severely ill patients.

Transfusions can cause sensitization to HLA antigens, creating a unique problem in potential kidney transplant patients. Studies have demonstrated increased sensitization of patients on a kidney transplant waiting list after transfusion, rendering them unsuitable candidates for living donation. Their only remaining alternative once this has occurred is to wait for a cadaveric graft, which takes up to four times longer, and may never receive a transplant. Hence, non-life-sustaining transfusions should be avoided in potential kidney transplant recipients [25].

Red blood cell transfusion is an independent predictor of systemic inflammatory response syndrome (SIRS), ICU admission, mortality, and length of hospital stay, and the development of multiple organ failure (MOF) [45]. In particular, the age of the blood plays an important role, with increased age of RBCs resulting in increased instances of MOF. RBCs are not alone in this adverse event. A multicenter prospective cohort study demonstrated that FFP was independently associated with increased risk of MOF and acute respiratory distress syndrome (ARDS) of 2.1% and 2.5% [46]. The same study found, however, decreased risk of MOF per unit of cryoprecipitate, and platelets were not found to be associated with MOF or ARDS [46].

In addition to MOF, blood transfusions are notorious in lay media for their association with infectious agents. In their review of the current literature, Englesbe et al. found that patients who received transfusions compared to those who did not experienced significant increase nosocomial infection rates, and each additional pRBC transfused correlated to increased infection risk [25]. Staphylococcus aureus is the most commonly transmitted bacterial pathogen [16]. Bacterial pathogen in blood products arise mainly from donor skin, and platelets are especially prone to these contaminants [35]. However, bacterial infections are less common than viral infections in blood transfusions.

Despite increased screening and testing, each RBC transfusion is associated with a risk for viral infections such as hepatitis [29]. Virus risks in the UK in FFP have been estimated at 1 in 8 million for HIV, 1 in 30 million for HCV and 1 in 900,000 for HBV [35]. Since up to 50% of adult donors are cytomegalovirus (CMV) carriers, there is a risk of transmission of this virus to patients, especially the immunosuppressed, transplant patients and neonates [35]. Compared to viral causes, bacterial, endotoxin and prion contamination rates are more rare [35]. In order to avoid this deleterious complication, virus-inactivated preparations of plasma exist, such as methylene blue and solvent-detergent treated products. While these options may offer increased viral protection, they have been associated with loss of clotting factors [35]. The most stringent testing protocols and sensitive tests may not ever eradicate the risk of infectious agent transmission due to several reasons. First, new pathogens of unknown methods of spread are constantly emerging and may not actively be screened for in its early emergence, such as human immunodeficiency virus (HIV) and West Nile virus. Another obstacle in prevention is the incubation period of pathogens before seroconversion of blood [29].

Prion diseases transmitted by transfusion has been a concern in the UK, following the bovine spongiform encephalopathy (BSE) epidemic. Unfortunately, no screening test for this condition has been established, and the occurrence of prion diseases in blood products in the UK is largely unknown. In order to avoid transfusions with prion disease, plasma has been imported from the USA since 2002 for pediatric transfusions [35].

Another concerning complication is the loss of efficacy in stored blood, and the adverse effects it causes. These consequences of the storage process are known as a storage lesion. With current technology, the shelf life of red blood cells cannot be extended further than its physiological shelf life of 120 days, and 35 and 42 days is the limit of viability in whole blood and adenine-saline preservation, respectively [29]. Even this length of shelf-life results in counterproductive transfusions. Specifically, RBC products older than 2 weeks have been shown to not improve oxygen uptake in septic patients. In fact, RBCs of that age have been associated with higher mortality, increased adverse events, extended hospital stay, and electrolyte imbalances. This reduction in efficacy may be due to decreased ability of the older RBCs to unload oxygen [29]. Another proposed mechanism is that since stored RBCs have depleted nitric oxide, this may have a vasoconstrictive effect, leading to thrombosis and the observed increases in venous and arterial thrombotic events in patients with increased pRBC and platelet transfusions [42]. The question is how realistic it is to maintain strict storage age in a finite and scarce resource such as blood. A double-blind, prospective randomized pilot study demonstrated that controlling the storage age of RBCs in transfusion compared to the current standard of care is feasible and results in decreased exposure to older blood [47]. More evidence is needed to determine precisely the cut off age of RBCs in their efficacy and availability. In stored platelets, it has been estimated that the recovery rate of 5-day old platelets is about 50%, with many nonviable platelets being sequestered into the spleen [21]. For these reasons, there is some concern that platelet counts performed immediately after transfusion do not provide an accurate picture of platelet function [21].