Nearly 2 decades have passed since the hemostatic resuscitation concept revolutionized the management of hemorrhagic shock. Pioneered by the US military during combat operations in Iraq and Afghanistan, this strategy pivoted from traditional resuscitation methods relying mainly on administering crystalloids and red cells to a more hemostatic regimen involving the transfusion of blood components in a balanced 1:1:1 ratio of plasma, platelets, and red blood cells, more closely recreating the composition of whole blood.1 This novel approach has been instrumental in mitigating the early stages of trauma-induced coagulopathy by promptly replenishing coagulation factors and platelets. Moreover, it has played a critical role in reducing the incidence of dilutional coagulopathy, a phenomenon prevalent with crystalloid-based resuscitation. This concept of hemostatic resuscitation was rapidly adopted in civilian trauma centers.2 Massive hemorrhage protocols (MHPs), also known as massive transfusion protocols, were developed and adopted to facilitate logistical challenges of timely delivery of set ratios of blood products. But massive hemorrhage does not only exist in the domain of trauma. Hence, MHPs originally developed for trauma were rapidly embraced in other settings, most predominantly in obstetric-related and gastrointestinal bleeding. In fact, the majority of MHP activations in hospitals across the country are for nontraumatic hemorrhage.3
It was recognized that 1:1:1 ratios of component therapy aimed at reconstituting the whole blood (Table 1). Hence, the next logical intervention was to start using whole blood in the resuscitation of injured and bleeding military personnel. As early as the US Civil War, the US military used whole blood for the resuscitation of injured patients.4 Both fresh whole blood and cold-stored whole blood have been used in multiple conflicts. The Committee on Tactical Combat Casualty Care, which dictates the appropriate resuscitation of combat victims in the field, has determined that low-titer whole blood remains the highest priority, followed by fresh whole blood, and finally by component therapy given in 1:1:1 ratio of plasma to platelets to red blood cells.5 Similarly, the Eastern Association for the Surgery of Trauma recently published practice management guidelines that conditionally recommend resuscitation with whole blood in civilian trauma patients requiring transfusion.6 Interestingly, whole blood was the mainstay of hemorrhagic shock resuscitation from the 19th century until the Vietnam War in civilian practice. The shift to component therapy-based resuscitation strategies occurred not because of demonstrated superiority or equivalence but due to advances in fractionation. These advances allowed for longer shelf-life of blood components, making them more readily available for remote conflicts—a change quickly embraced by the US military. In civilian settings, the fractionation of blood products maximized the utilization of each donated unit, prompting regional Red Cross Blood Centers to prioritize blood components and largely abandon the use of whole blood, even for patients in hemorrhagic shock.4 In this narrative, we revisit the role of whole blood transfusion in the management of nontraumatic hemorrhage, a practice poised to disrupt long-standing norms of hemostasis management.
| Whole blood | Component therapy | |
|---|---|---|
| Volume | 500 mL | 680 mL |
| Hematocrit | 38%–50% | 29% |
| Platelet count | 150,000-400,000 | 80,000 |
| Coagulation factors | 100% of initial concentration | 65% of initial concentration |
| Fibrinogen | 1000 mg | 1000 mg |
| Components | Not applicable | 1 unit PRBCs 1 unit platelets 1 unit fresh frozen plasma 1 unit cryoprecipitate |
| Cost | $200–300 | $810–1130 |
Envisioning the future of hemostatic resuscitation in the civilian realm relies on integrating whole blood for nontrauma scenarios. This shift is predicated on several compelling factors. Primarily, there is an expanding comfort level with whole blood within trauma centers, a trend that is gaining momentum as its application stretches beyond trauma care, as evidenced by emerging literature.7,8 Additionally, several well-designed prospective studies are comparing the effectiveness of whole blood to component therapy in civilian trauma settings.9 The pivotal focus of these studies is not to prove the superiority of whole blood but to demonstrate its equivalency to component therapy. Consequently, it stands to reason that—should these studies find no evidence of inferiority—whole blood may emerge as a preferred resuscitation medium, potentially shaping future clinical practice. Such preference for whole blood will be based on the simplified logistics of administering balanced hemostatic resuscitation, a reduced chance of clerical errors, and a lower antigen load due to limited donor exposure.
As data on the use of Low-Titer Group O Whole Blood (LTOWB) in civilian trauma accumulate, we may soon gain more information on the indications and scope of its use for nontraumatic hemorrhage (Table 2). Consistently, LTOWB demonstrates a safety profile in emergent settings that aligns with that of component therapy despite usually being used in more severely injured patients.10 The occurrence of clinically significant hemolytic transfusion reactions and other transfusion-related complications remains low.6 This can be attributed to its inherent compatibility with most recipients, the presence of floating (not fixed to red cells) antigens in recipients, and the low antibody titers in the transfused blood. Floating A and B antigens, or secretors, are soluble antigens present in plasma that do not bind to red blood cells, reducing the likelihood of immune recognition and subsequent reaction during transfusions. This characteristic helps limit the chance of hemolytic transfusion reactions when LTOWB is transfused, as these soluble antigens can neutralize antibodies without triggering a significant immune response. Although a comprehensive discussion of the underlying immunological mechanisms is not presented here, emerging evidence supports the safe use of RH+ LTOWB even in RH– women of childbearing potential. The risk of alloimmunization leading to conditions such as hydrops fetalis is considerably low when weighed against the immediate, life-saving benefits for the mother. Previously, the risk of alloimmunization in healthy Rh-negative recipients was thought to be as high as 80%. However, a recent study on emergency transfusions demonstrated alloimmunization rates of approximately 3% in this group. The probability of an Rh-negative mother carrying an Rh-positive fetus is about 60%, with a fetal death risk of approximately 4%. This translates to an overall alloimmunization and fetal death rate of less than 0.3%, or less than 1 death for every 300 Rh-negative women transfused with Rh-positive blood. Considering emergency transfusion rates at a large trauma center like San Antonio, it would take 750 years for 1 fetal death due to alloimmunization, while the provision of LTOWB would save the lives of 1500 women in the same period.11
| Study | Design | Population | WB (n) |
Component (n) |
Conclusions |
|---|---|---|---|---|---|
| Cotton et al12 | RCT | Adult patients requiring MHP activation in ED | 55 | 52 | Reduced transfusion at 24 h in WB group, no difference in mortality |
| Shea et al16 | Prospective observational |
MHP activation in trauma patients | 44 | 42 | WB associated with decreased RBC and plasma requirements, reduced mortality at 24 h and 28 d on regression analysis. |
| Brill et al17 | Prospective observational | Adults who received emergency-released blood products prehospital or in ED | 840 | 537 | WB associated with reduced product use at 24 h and adjusted 30-d survival |
| Sperry et al10 | Multicenter prospective observational | Patients who required MHP activation and damage controlled procedures | 624 | 427 | WB associates with lower 4-h, 24-h, and 28-d mortality in those with elevated probability of mortality |
| Torres et al18 | Retrospective | TQIP analysis of adult trauma patients in shock, who received at least 4 units of PRBCs in first hour. | 432 | 2353 | WB associated with improved 24-h and 30-d mortality. |
While the anticipated reduction in mortality from the use of whole blood in civilian trauma care has not been conclusively demonstrated, the confounding factor of a high incidence of traumatic brain injury-related fatalities may be obscuring the full picture.12 It is conceivable that in cases of nontraumatic hemorrhage, where traumatic brain injury does not complicate the clinical scenario, the benefits of whole blood transfusion on survival could be more readily apparent.
There is a consistent body of evidence indicating that the use of LTOWB in trauma care correlates with a decrease in the volume of blood products required, and this is achieved without a rise in complication rates.13 Should such outcomes be mirrored in the context of nontrauma care, it could potentially lead to widespread acceptance of LTOWB. This evolution would echo blood banks’ historical embrace of MHPs, which gained traction mainly due to their demonstrated efficiency in reducing blood product usage and wastage. Additionally, LTOWB offers significant logistical advantages. While maintaining a balanced ratio of 1:1:1 in blood components may seem straightforward theoretically, the reality of emergency care, with the pressures of hemorrhage and shock, often complicates this task. The question often arises in nontrauma transfusions as to when to switch to this balanced ratio from packed red blood cells (PRBCs) and crystalloid resuscitation—a clear approach remains elusive. Implementing LTOWB circumvents this issue, simplifying the resuscitation process, addressing logistical complexities, and potentially mitigating coagulopathies associated with the other bleeding diatheses.
The adoption of whole blood presents a particularly valuable advantage for trauma centers and hospitals in rural areas where resources are scarce. In such settings, access to a sufficient stock of components needed for hemostatic resuscitation, such as platelets, fresh frozen plasma (FFP), and cryoprecipitate, can be severely limited due to cost and unpredictability of utilization. This poses significant challenges in emergency procedures like craniotomies or laparotomies when sudden catastrophic bleeding occurs. Whole blood, with its comprehensive spectrum of coagulation factors and longer shelf-life as compared to platelets, thawed plasma, and thawed cryoprecipitate, offers a practical and effective resuscitation option that is both intuitive and safe for actively hemorrhaging patients. This inventory of LTOWB may be rotated between remote hospitals and trauma centers for the units nearing expiration. The cruise line industry, particularly Royal Caribbean, has acknowledged the benefits of a whole blood program, which has been instrumental in saving lives since 2008.14
Incorporating cost estimates into the discussion about adopting whole blood, particularly in settings with limited resources, adds a crucial dimension to the debate. While the separation and distribution of blood components from a single unit of whole blood have traditionally been viewed as more profitable for blood suppliers, the economic landscape may shift with the growing acceptance and demand for whole blood.15
The costs of blood components can vary widely, but some general observations are worth noting. For example, platelets have a short shelf-life of up to 7 days and must be stored at room temperature, requiring constant agitation to prevent clumping, thus presenting logistical costs in addition to their production costs. Even with the recent introduction of cold-stored platelets, which have a shelf-life of up to 14 days, their storage duration is still significantly less than LTOWB. Plasma, however, can be frozen and stored for up to a year, potentially offering more storage flexibility than other components. Whole blood has a shelf-life of 21 to 35 days, depending on the anticoagulant used, and contains all the components of blood, which can be used directly or separated into individual components as needed. The cost-effectiveness of using whole blood in trauma care, especially in emergent scenarios where a combination of RBCs, coagulation factors, and platelets are needed rapidly, might outweigh the traditional component separation model, especially when considering the logistical ease and potential reduction in waste due to expiration. While a single unit of whole blood can often be more directly applicable in emergency situations, the financial considerations of transitioning from a component-based model to a whole blood model for nontrauma indications need to be carefully evaluated against the backdrop of improved patient outcomes and potential for streamlined logistics. Each institution must assess these factors based on specific circumstances, including the frequency of emergency situations requiring transfusions, the availability and turnover of blood components, and the transfusion support needs of individual clinical services.15
It is essential, however, to exercise caution. The argument is not for whole blood to replace component therapy across the board. Rather, the use of whole blood is recommended during the acute phase of resuscitation for actively bleeding patients. Once the bleeding is controlled, component therapy, preferably goal-directed with viscoelastic testing, remains the standard of care for other hospital settings, such as managing severe anemia and addressing specific coagulation deficiencies.
In conclusion, reintegrating whole blood transfusion into nontrauma settings represents a significant paradigm shift in perioperative medicine. Its potential to improve patient outcomes, reduce transfusion requirements, and improve blood delivery logistics warrants a concerted effort from the medical community to address the challenges of adoption and expand the body of evidence supporting its use.
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