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. Author manuscript; available in PMC: 2022 Jan 1.
Published in final edited form as: Adv Emerg Nurs J. 2021 Oct-Dec;43(4):344–354. doi: 10.1097/TME.0000000000000376

Whole Blood for Resuscitation of Traumatic Hemorrhagic Shock in Adults

Allison R Jones 1, Justin L Miller 1, Jan Jansen 2, Henry E Wang 3
PMCID: PMC8555430  NIHMSID: NIHMS1730512  PMID: 34699424

Abstract

Injured patients with traumatic hemorrhagic shock often require resuscitation with transfusion of red blood cells, plasma and platelets. Resuscitation with whole blood (WB) has been used in military settings, and its use is increasingly common in civilian practice. We provide an overview of the benefits and challenges, guidelines, and unanswered questions related to the use of WB in the treatment of civilian trauma-related hemorrhage. Implications for advanced practice nurses and nursing staff are also discussed.

Keywords: whole blood, blood transfusion, trauma, injury

Trauma is a leading cause of death and exsanguination is the primary preventable cause of death in the first 24 hours after injury (Caspers et al., 2018; Heron, 2018; Holcomb et al., 2015). As such, replacement of lost blood is key to restoring cellular perfusion, hemodynamic stability, and affording time for surgical interventions to stop bleeding (Auten et al., 2015). Patients with severe injury may require massive transfusion or large volume transfusion (traditionally defined as 10 or more units of packed red blood cells in a 24-hour period) of blood or blood products (Hsu et al., 2016). In fact, some of the most critical patients can require more than 20 units (about 5 liters) of blood in the first 24 hours following injury (Cotton et al., 2013). Blood products used in massive transfusion or large volume transfusion generally include packed red blood cells (PRBCs), fresh frozen plasma, and platelets, collectively known as component therapy (CT). Use of additional products such as cryoprecipitate may be required based on the patient’s degree of coagulopathy. Understandably, the severity of injury and subsequent profound blood loss lead to higher mortality risk in patients receiving large volume transfusion, approaching 15% at 24-hours and 24% at 30-days (Meyer et al.).

In current practice, clinicians customarily treat hemorrhagic shock with CT with the goal of achieving a 1:1:1 ratio of PRBCs, fresh frozen plasma, and platelets (1:1:1) to approximate the make-up of whole blood (WB) (Holcomb et al., 2015). However, military healthcare providers have innovated the use of unseparated fresh WB as an acceptable alternative to CT in austere and forward surgical environments when providing trauma resuscitation. WB offers logistical advantages, providing all elements of CT (PRBCs, plasma, platelets) in a single product, and select studies suggest potentially better outcomes with WB than CT. While once not considered practical in the civilian setting due to storage and administration limitations, system developments over the last 5 years have enhanced the availability of WB. Today a handful of civilian trauma centers and Emergency Medical Services systems have adopted the use of cold-stored WB. We provide an overview of WB and practical guidelines for its application in current emergency department practice.

What is Whole Blood?

WB is blood that has not been separated into its individual components (red blood cells, plasma, and platelets). However, in practice there are different formulations of WB. Fresh or unrefrigerated WB is blood that is infused shortly after donation. Fresh WB is used almost exclusively in the military setting where pre-screened personnel may donate blood products as it is needed for the care of hemorrhaging patients (Auten et al., 2015; Ho & Leonard, 2011; Keneally et al., 2015; Meyer et al., 2017; Nessen et al., 2013; Perkins et al., 2011; Spinella et al., 2009). In civilian practice, only cold-stored WB is used, preserved with either citrate phosphate dextrose or citrate phosphate dextrose adenine (American Association of Blood Banks et al., 2017; Ho & Leonard, 2011; Spinella et al., 2016). The definition of WB varies within the literature (Cotton, et al., 2013; Ho & Leonard, 2011; Jones et al., 2014; Keneally et al., 2015; Perkins et al., 2011; Seheult et al., 2018; Yazer et al., 2016). The most commonly used type of WB is type O. Low-titer type O WB (LTOWB) refers to WB which contains type O red blood cells and plasma containing low levels of anti-A and anti-B antibodies, making it safe to transfuse to a patient with any blood type. Group O blood can be Rhesus-positive (Rh+) or Rhesus-negative (Rh-).

Stored WB used in civilian settings may be leukocyte-reduced (removal of white blood cells) prior to transfusion to reduce the risk of inflammatory complications in the transfused recipient, including the risk of HLA alloimmunization, CMV transmission, and febrile non-hemolytic transfusion reactions (Spinella et al., 2016). Though leukoreduction can reduce the risk of inflammatory reactions and disease transmission, leukoreduction also destroys and removes platelets, potentially worsening the patient’s ability to form blood clots. Platelet-sparing filters, though commonly used in preparing LTOWB units for storage, are associated with reduction in number and function of platelets (Pidcoke et al., 2013). In addition, a recent analysis by Remy and colleagues found no difference in platelet concentration of leukoreduced vs non-leukoreduced LTOWB at storage days 10 and greater. Therefore, transfusion of stored leukocyte-reduced WB may require the additional transfusion of platelets or clotting factors in order to achieve hemostasis. Of note, platelet-poor LTOWB is also available, Concerns have been raised regarding the impact of leukoreduction on hemostatic performance as well, since leukoreduction also reduces the storage life of red blood cells. Limited evidence exists to support the use or avoidance of leukoreduction in stored WB. In fact, recent findings from a study by Fadeyi et al. (2020) comparing outcomes based on use of leukocyte-reduced vs non-leukocyte-reduced LTOWB found no difference in 24-hour survival among 167 patients who received a total of 271 LTOWB transfusions. Currently, the use of leukocyte reduction with WB remains controversial (Fadeyi et al., 2020) and the storage of LTOWB varies between programs.

In current practice, the U.S. military uses fresh WB (WB stored for less than 24 hours) for resuscitation when CT is not available or feasible. Military personnel – who are screened for potential bloodborne diseases and determination of blood type prior to deployment or every 90 days during deployment (American Association of Blood Banks et al., 2017) – act as immediately available “walking blood banks,” providing direct transfusion of their blood to trauma victims as needed (Morris et al., 2019; Nunez et al., 2009).

After years of fresh WB use in the military setting and noted benefits for patient outcomes, blood bankers and clinicians began to reconsider the use of WB in the civilian setting. Traditionally, use of WB in the civilian setting was associated with storage and preservation challenges among blood bankers, as the “walking blood bank” used in the military was not a feasible option.

History of Whole Blood Resuscitation

Use of WB in human patients has been documented since the 17th century when blood from lambs was transfused to men with various health issues, including one with mental illness (Perkins et al., 2011). The first human-to-human WB transfusion was not until 1818, when physicians began experimenting with transfusion for treatment of cancer and postpartum hemorrhage (Nessen et al., 2013). After that, WB transfusion was primarily used in the field of obstetrics until World War II when Soviet, British, and United States governments implemented transfusion programs to address the need for treatment of wounded soldiers at the front lines (Ho & Leonard, 2011; Spinella et al., 2016).

In 1941, Edwin Cohn and his team published a review article based on their studies of separating plasma proteins from units of WB (Spinella et al., 2016). Their work was rapidly developed with the outbreak of World War II and the threat of U.S. involvement. The goal was to identify a product that could be shipped in bulk, did not require refrigeration, and would prevent death due to hemorrhage. What is known today as CT was not truly established until 1951 after the creation of the first cell separator, allowing WB to be split into PRBCs, plasma, and platelets (Spinella et al., 2009). The advent of CT drastically changed the face of resuscitation practices, allowing providers to tailor treatment for patients based on perceived need, such as transfusing PRBCs for anemia or platelets to promote clotting.

Considerations for Whole Blood Use

Whole Blood Administration and Safety

While there are no clearly defined indications, clinicians usually reserve WB for use in critically ill patients with substantial blood loss. Hemorrhagic shock is often diagnosed based upon the combination of patient injury pattern, vital signs, clinical presentation, estimated amount of blood loss, and mental status (Auten et al., 2015; Cotton et al., 2013; Holcomb et al., 2015; Keneally et al., 2015; Meyer et al., 2017; Perkins et al., 2011). The Assessment of Blood Consumption (ABC) score is commonly used as a decision support tool for activation of massive transfusion protocols as it incorporates the mechanism of injury (blunt vs penetrating), blood pressure and heart rate on admission to the emergency department, and results of a Focused Assessment with Sonography for Trauma (Morris et al., 2019). ABC scores may range from 0–4 and patients with a score of ≥2 are likely to require massive transfusion. WB potentially may also potentially be used for less critical patients (Nunez et al., 2009).

WB may be transfused as soon as it is available. WB can (and should) be given quickly, but units should be transfused using a rapid infuser or fluid warmer approved by the US Food and Drug Administration (or equivalent regulatory body in other countries) to avoid iatrogenic hypothermia. Multiple units of WB may be given as needed. Giannoudi and Harwood (2016) recommended supplementing leukoreduced, stored WB with platelets. Cryoprecipitate may still be required. While there is no limit to the quantity of WB that may be transfused, hospitals usually maintain only a limited number of WB units. When WB supplies do run out and additional blood replacement is required, clinicians may revert to CT.

WB transfusion also reduces the amount of non-therapeutic fluid (i.e., preservative solution) administered to patients. For example, a single unit of stored WB contains approximately 500 mL of fluid including preservative solution, while the equivalent CT combination of 1 unit PRBCs, platelets and plasma would equal roughly 650 mL (350 mL packed red blood cells, 50 mL platelets, and 250 mL plasma) (Ho & Leonard, 2011). In fact, investigators estimate that transfusion of CT in a 1:1:1 manner results in a 38% loss of plasma coagulation factor concentration, 56% loss of platelets, and a 17% loss of red blood cells relative to WB (Mays & Hess, 2017). In other words, patients receive an extra 100 mL of fluid that lacks both coagulation factors and oxygen-carrying cells per reconstituted unit of WB.

Blood Type Compatibility

As with PRBCs, transfused WB must be type and Rh compatible. However, while group O-negative PRBCs can be transfused to patients with any blood type and Rh factor, group O-positive WB contains plasma with anti-A and anti-B antibodies, which can trigger hemolytic transfusion reactions in patients with type A, B, or AB blood. Roughly half of the US population has type O blood (48%), but only an estimated 14% are Rh-negative; logistically speaking, this equates to a higher likelihood of blood centers collecting and distributing Rh-positive blood. Accordingly, while O-negative blood is recognized as the universal donor, it is more likely that patients will receive O-positive blood in emergencies. Transfusion of Rh-positive blood to a Rh-negative woman of childbearing potential carries with it the risk for development of anti-Rh antibodies and harm to a future pregnancy (Thomas et al., 2019). Therefore, some centers preferentially give WB to young males and avoid its administration to females <50 years of age (Thomas et al., 2019). However, it should be noted that data on adverse reactions to O-positive blood are rare, with the benefit of resuscitation and hemostasis outweighing the risk of hemolytic transfusion reactions.

To mitigate hemolytic transfusion reactions, most centers use only LTOWB where antibodies are below a predetermined threshold. However, the threshold for safe “low titer” levels is not defined by blood regulatory agencies and therefore varies widely among institutions, with commonly used values ranging from <50 to <100 (Seheult, Bahr, et al., 2018; Thomas et al., 2019; Yazer et al., 2016). Findings from a recent clinical investigation on the use of stored WB in trauma revealed no transfusion reactions among 172 patients who received a total of more than 700 units of stored WB (Yazer et al., 2016). Although recent findings suggest leukoreduction of WB may be beneficial in reducing the risk of transfusion reactions, organ failure, infections, and other inflammatory complications, certain methods of leukoreduction are also associated with decreased hemostatic effects (Bianchi et al., 2016; Giannoudi & Harwood, 2016; Seheult, Anto, et al., 2018).

While Rho(D) Immune Globulin provides protection to Rh-negative women pregnant with Rh-positive children, the prescribed dose was developed to combat antibodies contained in the plasma of blood contained in the umbilical cord or one unit of PRBCs, roughly only 10 mL (Bilgin et al., 2011). A scaled dose of Rho(D) Immune Globulin to combat antibodies delivered through multiple units of WB (each containing 200–300 mL of plasma) is not currently available and likely not feasible (Bilgin et al., 2011). However, preliminary evidence exists to support positive patient outcomes after use of Rh+ LTOWB in postpartum hemorrhage with O-negative women (Strandenes, Berseus, et al., 2014).

Benefits to Patient Outcomes

A potential benefit of WB transfusion is the immediate delivery of coagulation factors necessary for hemostasis, including fibrinogen, fibronectin, factors V, VII, VIII, XIII, and von Willebrand factor. Resuscitation using CT requires administration of fresh frozen plasma and cryoprecipitate along with PRBCs in order to provide patients with clotting factors depleted due to injury. This combination therapy presents a significant practical challenge, requiring clinicians to achieve a balance between the patient’s fluid volume status and their hemostasis. Hypothetically, through more immediate and concentrated delivery of coagulation factors, patients who receive WB will reach hemostasis more quickly, be exposed to less non-therapeutic fluid, and experience a decrease in morbidity and mortality. In addition, the use of a single product may reduces exposure to multiple blood donors and reduces the risk of hemolytic transfusion reactions in the recipient.

Although conceptually attractive, the relationship between WB use in trauma and its impact on patient outcomes has yet to be confirmed. Some evidence exists to support several benefits associated with the use of WB as compared to the use of CT in patients with major trauma (Bahr et al., 2019; Jones & Frazier, 2014, 2017). Investigators estimate that transfusion of CT in a 1:1:1 manner results in a 38% loss of plasma coagulation factor concentration, 56% loss of platelets, and a 17% loss of red blood cells relative to WB (Jones & Frazier, 2014).

Current data supporting improved outcomes associated with the use of WB in trauma are limited and complex. Between 2007–2019 only 12 studies have compared outcomes (e.g., 24-hour or in-hospital/30-day mortality, intensive care unit length of stay) between those who received WB and CT (Table 1) (Auten et al., 2015; Cotton et al., 2013; Ho & Leonard, 2011; Jones & Frazier, 2014, 2017; Keneally et al., 2015; Mays & Hess, 2017; Meyer et al., 2017; Nessen et al., 2013; Perkins et al., 2011; Seheult, Anto, et al., 2018; Seheult, Bahr, et al., 2018; Spinella et al., 2009; Thomas et al., 2019; Williams et al., 2019; Yazer et al., 2016; Zhu et al., 2019). Importantly, the definitions and types of WB used among institutions varied widely (Table 2). In addition, the majority of studies were observational with the exception of one randomized controlled trial by Cotton et al. (2013). Of note, the randomized trial was developed to assess the feasibility of the use of modified WB, meaning units were refrigerated for 5 days prior to use and were leukoreduced leading to platelet dysfunction and removal. The trial by Cotton et al. was also conducted in the civilian trauma setting and was not powered to detect differences in mortality outcomes among patients who were transfused with modified WB compared to CT.

TABLE 1.

Studies Examining the Use of Whole Blood

Source Methods Major Findings
Auten et al. (2015) Retrosp. cohort study, military (Afghan.)
Patients required MT, with ISS ≥ 15
Compared non-leukoreduced FWB + CT (n=26) to CT only (n=35)		 No difference in 24h and 30d mortality
Coagulopathy less common in FTB +CT group
Cotton et al. (2013) RCT of civilian US trauma
Patients transfused ≤ 4U 1hr, Level 1 trauma
Compared mWB + PLT (6:1) (n=55) to PRBC + FFP + PLT (6:6:1) (n=52)		 Reduced 24-hour transfusion requirements in WB group, but only for patients without TBI
No difference in 24h and 30d mortality
Ho & Leonard (2011) Retrosp. cohort study of civilian Australian trauma
Patients required MT
Compared UYWB (n=77) to CT (n=276)		 No difference in in-hospital/30-day mortality
Increased ICU and hospital length of stay among UYWB patients
Jones et al. (2014) Retrosp. cohort study of civilian US trauma
Patients transfused ≥ 1U, ISS ≥ 25
Compared WB (n=83) to CT (n=1662)		 No difference in in-hospital mortality
Keneally et al. (2015) Retrosp. cohort study, military (Afghan., Iraq)
Patients transfused ≥ 1U, CRTT
Compared WFWB + CT (n=281) to CT (n=3656)		 Increased in-hospital mortality among patients who received WFWB + CT
Nessen et al. (2013) Retrosp. cohort study, military (Afghan.)
Patients transfused ≥ 1U
Compared FWB + pRBC + FFP (n=94) to PRBC + FFP (n=394)		 No difference in in-hospital mortality
Perkins et al. (2011) Retrosp. cohort study, military (Iraq)
Patients required MT
Compared FWB (n=85) to aPLT (n=284)		 No difference in 24h and 30d mortality
Higher incidence of ARDS in FWB group
No differences in multiorgan failure, infection, venous/arterial embolic events
Seheult et al. (2018) Retrosp. cohort study of US civilian trauma
Patients transfused ≥ 1U
Compared LTO-WB or LTO-WB + CT (n=135) to CT (n=135)		 No difference in 24h and in-hospital mortality
No difference in acute kidney injury
Spinella et al. (2009) Retrosp. cohort study, military (Afghan., Iraq)
Patients transfused ≥ 1U
Compared WFWB + pRBC + FFP (n=100) to CT (n=254)		 Improved 24h and 30d survival in WFWB group
Renal failure more common in WFWB group
No difference in DVT and ARDS
Williams et al. (2019) Prospec. observ. of US civilian trauma
Patients transfused ≥ 1U
Compared LTO-WB (n=198) to RBC and/or FFP (n=152)		 No difference in 30d mortality
No difference in hemolysis panel values
Yazer et al. (2016) Retrosp. cohort study of US civilian trauma
Patients transfused ≥ 1U
Compared LTO-WB or LTO-WB + CT (n=47) to CT (n=145)		 No difference in in-hospital mortality
No difference in transfused volume when TBI patients included; reduced transfused volume with LTO-WB when TBI excluded
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aPLT = apheresis platelets, ARDS = acute respiratory distress syndrome, CRTT = combat related thoracic trauma, CT = Component therapy, FFP = fresh frozen plasma, FWB = Fresh Whole blood, ICU = intensive care unit, ISS = injury severity score, LTO-WB = Low-titer group o-negative whole blood, MT = Massive transfusion, mWB = modified whole blood, PLT = platelets, pRBC = packed red blood cells, TBI = traumatic brain injury, WFWB = warm FWB, UYWB = unrefrigerated young whole blood

*Indicates data for total patients in the study

TABLE 2.

Definitions of Whole Blood

Whole Blood Type Source Description Preparation/Storage/Administration
Group O Blood Yazer et al..(2016) Male donor type O+ blood • Stored between 1–6°C (33.8–42.8°F)
• Anti-A and anti-B titers <100
Seheult et al. (2018) Male donor O+ blood • PLT sparing leukoreduction system
• Anti-A and anti-B of less than 50
Fresh Whole Blood Keneally et al. (2015) Warm fresh whole blood described as “PLT, plasma, and RBCs in a normal physiologic ratio” • Not provided
Perkins et al. (2011) Non-leukoreduced whole blood • Stored at 22°C (73.4°F) for ≤24 hours
Unrefrigerated Young Whole Blood Ho & Leonard (2011) Whole blood • Stored between 20–24°C (68–75.2°F)
• Transfused within 24 hours of donation
Modified Whole Blood Cotton et al. (2013) Whole blood • Leukoreduced with nonfunctioning PLT
• One unit of apheresis PLT transfused with every 6 units of whole blood
Whole Blood – Not Otherwise Specified Jones et al. (2014) Not provided Not provided
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PLT=platelets; RBC=red blood cells

In a large retrospective analysis of patients treated at combat hospitals for thoracic trauma (n=3,937), Keneally et al. (2015) compared mortality rates among patients who received warm fresh WB plus CT (n=281) vs CT only (n=3,656). After controlling for demographic and injury severity covariates, the use of warm fresh WB plus CT was not associated with an increased mortality risk compared to CT only. Similarly, Williams et al. (2019) assessed the safety of LTOWB in a civilian trauma center for patients admitted over an 8-month period (n=350). Patients were divided into those who received any amount of LTOWB (n=198) vs those who received CT only (n=152). No differences were noted in mortality rates among the groups, but those who received LTOWB experienced more than a 50% reduction in post-emergency department blood product use compared to the CT only group. Importantly, findings from the 12 studies revealed no improvement in mortality with the use of WB compared to CT therapy. However, the non-randomized design and wide variation in WB definition of prior studies preclude a formal conclusion about WB effectiveness.

The most compelling advantage of WB may be its theoretical ease of administration compared with CT. Rather than having to issue three different products (PRBCs, plasma, platelets), blood banks only have to provide a single type of product, reducing work and the risk of administration errors. At the bedside it is also easier to administer one bag of WB rather than three different CT products. A summary of the pros and cons of WB use can be found in Table 3.

TABLE 3.

Pros and Cons of Whole Blood Use in Trauma Compared to Component Therapy


Pros
Cons

• Does not require Y-tubing or priming tubing with 0.9% Normal Saline
• Leukoreduced units should be supplemented with platelets
• Can be given quickly • Cryoprecipitate may still be required for hemostasis if the patient requires fibrinogen replacement
• Immediately ready for transfusion when available
• Limited storage time, resulting in higher quality product transfused and more viable cells		 • O-negative units contain plasma with anti-A and anit-B antibodies that can cause hemolytic reactions.
• Reduces amount of non-therapeutic fluid (i.e., preservative solution) transfused to the patient • Risk of Rh alloimmunization during future pregnancies when transfused to O-positive females
• Immediate delivery of coagulation factors not found in packed red blood cells; faster time to hemostasis
• Efficiency of transfusion (1-unit whole blood for every 3 units of components)
• Reduced risk of administration errors with fewer products transfused
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Implications For Nurses

Use of CT in a ratio that closely mimics WB (1 unit PRBC: 1 unit PLT: 1 unit FFP) significantly decreases six-hour mortality of patients with major trauma (Holcomb et al., 2013). Aside from the clinical benefits to the patient, use of WB presents opportunities for improved patient care on the part of both advanced practice nurses and staff nurses. For advanced practice registered nurses (APRN) , CT prescription – choosing which component to transfuse next -- may become complicated depending on the patient scenario, with many patients presenting to the trauma bay in a coagulopathic state. In addition, attention to the ratio in which CT is being delivered may distract from patient care or other pressing issues such as airway management. WB, therefore, presents a simplified method by which advanced practice nurses may address patient resuscitation in those who are expected to require large volume transfusion. Additionally, the APRN should maintain normal ionized calcium levels should be maintained during massive blood transfusions (Spahn et al., 2019). WB and CT are preserved using citrate (Giancarelli et al., 2016). Citirate binds with calcium causing hypocalcemia. Low calcium levels in the trauma patient is associated with increased mortality (Spahn et al., 2019).

For staff nurses, the use of WB theoretically improves patient safety through a number of mechanisms. First, use of WB decreases the number of safety checks that require two licensed providers, thereby decreasing staff nurses’ workload by two-thirds (one blood product vs three). Additionally, the logistics of WB resuscitation are theoretically easier than that of CT resuscitation in that it requires fewer products from the blood bank, fewer supplies (WB does not require Y-tubing or priming of tubing with 0.9% normal saline), less intensive monitoring for adverse reactions, and a generally simpler clinical scenario. Collectively, these factors highlight the benefits to provision of care among nursing staff, which will likely lead to a decrease in time and resources and promotion of patient outcomes.

Unanswered Questions

There are several questions related to use of WB in trauma resuscitation that have not been answered. The most important is whether WB is better than or as good as CT. It is also currently unclear whether WB resuscitation reduces the total transfusion volume required, whether it hastens time to hemostasis, and if it results in fewer inflammatory complications. To truly address this question, randomized trials are required in which patients with similar injury severities who are predicted to require massive transfusion are assigned to resuscitation using either WB or CT. Other questions include the administrative or logistical benefits of WB versus CT – is WB truly easier and faster to administer compared to multiple blood components? Could WB use result in greater efficiency of clinical care compared to CT? Finally, if WB does turn out to be clinically effective, cost-benefit analyses are required to inform practice change.

Acknowledgments

FINANCIAL SUPPORT AND ACKNOWLEDGEMENTS

Dr. Wang and Dr. Jansen receive grant support from award U34-HL148472 from the National Heart, Lung and Blood Institute.

Footnotes

CONFLICTS OF INTEREST

The authors do not report any related conflicts of interest.

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