Trauma, Prehospital Care, EMS

The Use of Low Titer Group O Whole Blood in Emergency Medicine

Trauma is the leading cause of death for people ages 46 and younger in the U.S. - yet up to 20% of trauma deaths are potentially survivable. Can the use of low titer Group O whole blood improve outcomes?

Trauma is the leading cause of death for ages 46 and under in the U.S. — yet up to 20% of trauma deaths are potentially survivable.1 Aside from surgical intervention, these deaths are best mitigated through early hemorrhage control with tourniquets, hemostatic dressings, and an aggressive approach to damage control resuscitation (DCR).

For many years, the standard for DCR consisted of crystalloid solutions and red blood cells (RBCs). This standard in trauma resuscitation has evolved to include the use of balanced fluids and massive transfusion protocols (MTP) utilizing RBCs, fresh frozen plasma (FFP) and platelets (PLTs) in a 1:1:1 ratio (>10 units of RBCs in 24 hours).2 The use of 1:1:1 ratio protocols attempts to mimic the benefits of whole blood (WB) with individual components.

WB has been used on a mass scale for resuscitation of trauma patients since World War I.3 The U.S. Army documented the safety of group O WB as a universal product as early as 1917.4 While plasma and albumin were first favored by the U.S. forces in World War II, eventually WB was sent to the European and Pacific theaters.5 Military units also established walking blood banks at far forward settings through larger surgical hospitals. These efforts resulted in almost all transfusions being group O WB.6 Near the end of World War II, the Army Blood Program noted mild transfusion reactions in WB with IgM anti-A and anti-B titers >512 with one severe transfusion reaction of an IgM anti-A titer of 8000.4 In response, the Army Blood Program defined low titer group O whole blood (LTOWB) to help mitigate and eliminate further severe reactions. LTOWB is defined as with IgM anti-A and anti-B < 250.4 This program was carried over to Korea, where over 400,000 units of LTOWB were shipped from the U.S. and transfused to casualties.4

As blood fractionalization was developed, civilian blood banks shifted away from WB and toward component-based therapy due to risk of transfusion transmitted diseases (TTD), requirements for specific component therapy, and logistical issues.6 With this development, the use of crystalloids solutions for trauma resuscitation became more prevalent, especially in the prehospital setting. The consequence of mixing components and crystalloids in trauma resuscitation was an unbalanced approach, leading to iatrogenic coagulopathy, acidosis, and hypothermia, more commonly known as the “Lethal Triad.”7

In 2004, the concept of DCR was developed and implemented by the Department of Defense (DoD).8 This attempt to reconstitute whole blood using the 1:1:1 ratios in military trauma was aimed at the prevention and correction of trauma induced coagulopathy with minimal use of crystalloids.2

The conflicts in Iraq and Afghanistan revived an interest in fresh whole blood (FWB) for DCR during hemorrhagic shock. The use of FWB in combat demonstrated superior outcomes over component therapy.9-11 In 2014, the Committee on Tactical Combat Casualty Care recommended FWB as the preferred resuscitative product for DCR in hemorrhagic shock.12 In an effort to seamlessly provide FWB at the point-of- injury (POI), the U.S. Army’s 75th Ranger Regiment developed a LTOWB program in 2015.13 In 2016, due to the collection difficulties that can occur with FWB at the POI, the Armed Services Blood Program (ASBP) began collecting and shipping cold-stored LTOWB from Joint Base Lewis-McCord to units in Afghanistan.14 The use of cold-stored LTOWB is now being used in civilian sector emergency services, to include prehospital use.6,15-17 The AABB now recommends the emergency release and use of LTOWB in the setting of life-threatening hemorrhagic shock because of its advantages.18

What is Low-Titer Group O Whole Blood?
LTOWB is unseparated blood, collected from a donor with “low” IgM and/or IgG anti-A and anti-B and can either be stored or given fresh (within 8-24 hours). There is no universally accepted definition of LTOWB and the AABB states that low titer may be defined by institutions. The DoD and University of Texas San Antonio Health Sciences Center University Hospital define LTOWB as IgM anti-A and anti-B < 256. Cypress Creek EMS uses IgM anti-A and anti-B < 150. Finally, the University of Pittsburgh Medical Center used IgM anti-A and anti-B <  50.15-17

Internationally, in addition to IgM, IgG is often used to define low titer status. The presence or absence of the Rhesus (Rh) (D) antigen is much less relevant during hemorrhagic shock resuscitation; therefore, LTOWB is not defined by its Rh factor status. Rh negative patients do not develop sensitivity to Rh positive blood until weeks after exposure.16 Therefore, in the acute trauma setting, Rh positive blood can be administered to Rh negative patients without significant risk of transfusion reaction. Still, Rh negative is optimal for females of child-bearing age out of concern for sensitization that can cause hemolytic anemia of the newborn.

Advantages
Simplicity and less error
Evidence suggests that early (< 34 min from time of injury) administration of any blood product to severely injured patients has early survival benefit.19 It is important that clinicians understand this statistic defines the time from initial trauma, not the time the patient arrives to the hospital. Using blood products in the prehospital setting can therefore significantly reduce the lag time to WB infusion, which in turn can decrease mortality from trauma.

When using LTOWB, one bag is delivered versus a separate bag for each component for equivalent resuscitation efforts.20 When compared to ABO group-specific WB in emergent situations, LTOWB may expedite treatment due to reduction in time necessary for ABO typing and reduce the under-resuscitation that may happen when specific ABO groups are not available.21 Also, LTOWB use over group-specific WB reduces the likelihood of human error as well as the probability of severe blood cell and plasma-related transfusion reactions. The ease of administering one product, especially in the prehospital setting, therefore decreasing confusion in decision-making and tracking may facilitate resuscitation efforts in the field and emergency room, which could in turn translate to improved clinical outcomes.22,23

Savings
When preparing and storing components, whole blood is centrifuged to separate the red blood cells, plasma and platelets. RBCs are washed to remove proteins that did not remain with the plasma after centrifugation. Plasma is frozen but can be also be processed to make cryoprecipitate. This process can be costly, which is passed onto the patient.24,25

All blood is pre-tested for TTDs. LTOWB requires minimal interventions, but does require TTD, titer testing, and leukocyte reduction before use or storage. LTOWB has the potential to reduce logistical concerns regarding cost. There has been concern about the short shelf life of LTOWB and increase waste of the WB product, but these concerns can be mitigated as LTOWB is able to be separated into RBCs after a predetermined date to maximize use and eliminate waste.

Avoiding excess fluid
Additives and anticoagulants are required for any blood collection.  However, when components are used for MTP, they contain three times the additives and anticoagulants in terms of volume compared to whole blood.20 This excess anticoagulant and additives may cause a dilutional coagulopathy in patients receiving components. In situations where surgery might not be readily available, this additional fluid can raise a patient’s blood pressure to a level where it may cause previous formed clots to break, resulting in re-bleeding. Citrate, an anticoagulant added to blood collection bags, is metabolized by the liver and can lead to acidosis and hypocalemia.26

Disadvantages
Shelf life

Probably the greatest disadvantage of LTOWB is the shelf life. LTOWB is usually anticoagulated with citrate phosphate dextrose (CPD) and has a shelf life of 21 days. When citrate phosphate dextrose adenine (CPDA-1) is used in lieu of CPD, the shelf life is extended to 35 days.

However, platelet function drops after 14 days and significantly after 21 days.27 This is shorter than the shelf lives of PRBCs and FFP, which are 42 days and a year, respectively.2

Future research
There is significant data from the past 70 years on the use of WB and LTOWB for trauma resuscitation. Currently, the skepticism about the safety of LTOWB has resulted in new research. The most significant remaining issue is shelf- life extension. CPDA-1 can extend WB out to 35 days but does nothing for extending PLT function viability. Development of new anticoagulants and additives that will preserve WB functionality would greatly enhance this shortcoming.

The debate over safe titer levels is ongoing. At this time, among civilian hospitals utilizing LTOWB, there is a range of critical antibody titer thresholds varying from < 50 to < 256.15-17,28 Concerns with setting an antibody titer threshold that is too high may result in the increased possibility of transfusion reactions, whereas a threshold set too low may exclude many safe donors. International consensus of a scientifically-demonstrated safe threshold is needed.

In smaller communities or the military, there is concern over a change in donor titer status over time. Current literature shows there is no change in titer status with vaccinations and minimal variability titer levels.29,30 Unpublished data from the U.S. military shows titer changes do often occur, but there is a trend towards low titer. The question remains, should blood banks require titer testing on a regular basis?

Conclusion
While RBCs and FFP have longer shelf lives and are useful in specific conditions, LTOWB use in trauma and hemorrhagic shock has proven advantages over component therapy. It is less likely to cause a severe transfusion reaction, contains less anticoagulants and additives, causes less dilutional coagulopathy, is faster and easier to deliver, and is more cost effective to produce. Efforts should be made to implement LTOWB in prehospital medicine and for DCR in the emergency room.

Acknowledgments
The authors would like to thank Brandon M. Carius, MPAS, PA-C, for reviewing the manuscript and his valuable comments.


References

1. National Academies of Sciences E, Medicine. A National Trauma Care System: Integrating Military and Civilian Trauma Systems to Achieve Zero Preventable Deaths After Injury. Washington, DC: The National Academies Press; 2016.
2. Holcomb JB, Tilley BC, Baraniuk S, et al. 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. JAMA. 2015;313(5):471-482.
3. Robertson B. Further Observations on the Results of Blood Transfusion in War Surgery. Ann Surg. 1918;67(1):1-13.
4. Berseus O, Boman K, Nessen SC, Westerberg LA. Risks of hemolysis due to anti-A and anti-B caused by the transfusion of blood or blood components containing ABO-incompatible plasma. Transfusion. 2013;53 Suppl 1:114S-123S.
5. Kendrick DB. Blood Program in World War II. Washington, D.C.: Office of the Surgeon General; 1964.
6. Spinella PC, Pidcoke HF, Strandenes G, et al. Whole blood for hemostatic resuscitation of major bleeding. Transfusion. 2016;56 Suppl 2:S190-202.
7. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248(3):447-458.
8. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-310.
9. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB. Warm fresh whole blood is independently associated with improved survival for patients with combat-related traumatic injuries. J Trauma. 2009;66(4 Suppl):S69-76.
10. Murdock AD, Berseus O, Hervig T, Strandenes G, Lunde TH. Whole blood: the future of traumatic hemorrhagic shock resuscitation. Shock. 2014;41 Suppl 1:62-69.
11. Nessen SC, Eastridge BJ, Cronk D, et al. Fresh whole blood use by forward surgical teams in Afghanistan is associated with improved survival compared to component therapy without platelets. Transfusion. 2013;53:107S-113S.
12. Butler FK, Holcomb JB, Schreiber MA, et al. Fluid Resuscitation for Hemorrhagic Shock in Tactical Combat Casualty Care: TCCC Guidelines Change 14-01– 2 June 2014. J Spec Oper Med. 2014;14(3):30-55.
13. Fisher AD, Miles EA, Cap AP, Strandenes G, Kane SF. Tactical Damage Control Resuscitation. Mil Med. 2015;80(8).
14. Warner N, Zheng J, Nix G, et al. Prehospital Use of Group O Low Titre Whole Blood. J Spec Oper Med. 2018;18(1):15-18.
15. Yazer MH, Jackson B, Sperry JL, Alarcon L, Triulzi DJ, Murdock AD. Initial safety and feasibility of cold-stored uncrossmatched whole blood transfusion in civilian trauma patients. J Trauma Acute Care Surg. 2016;81(1):21-26.
16. Dodge M, Thompson D, Bank EA, Nealy W, Fisher AD. Whole Blood in EMS May Save Lives. Journal of Emergency Medical Services. 2018(February):50-55.
17. McGinity AC, Zhu CS, Greebon L, et al. Pre-hospital Low Titer Cold Stored Whole Blood: Philosophy for Ubiquitous Utilization of O Positive Product for Emergency Use in Hemorrhage due to Injury. J Trauma Acute Care Surg. 2018.
18. Emergency Release Low Titer O Whole Blood Is Now Permitted by AABB Standards [press release]. The Trauma Hemostasis and Oxygen Research (THOR) Network, January 7, 2018 2018.
19. Shackelford SA, Del Junco DJ, Powell-Dunford N, et al. Association of Prehospital Blood Product Transfusion During Medical Evacuation of Combat Casualties in Afghanistan With Acute and 30-Day Survival. JAMA. 2017;318(16):1581-1591.
20. Armand R, Hess JR. Treating coagulopathy in trauma patients. Transfusion Medicine Reviews. 2003;17(3):223-231.
21. Strandenes G, Berseus O, Cap AP, et al. Low titer group O whole blood in emergency situations. Shock. 2014;41 Suppl 1:70-75.
22. Cap AP, Pidcoke HF, DePasquale M, et al. Blood far forward: Time to get moving! J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S2-6.
23. Holcomb JB. Transport Time and Preoperating Room Hemostatic Interventions Are Important: Improving Outcomes After Severe Truncal Injury. Crit Care Med. 2018;46(3):447-453.
24. Shander A, Hofmann A, Ozawa S, Javidroozi M. The True Cost of Red Blood Cell Transfusion in Surgical Patients. Blood. 2008;112(11):3045-3045.
25. Campbell HE, Stokes EA, Bargo DN, et al. Quantifying the healthcare costs of treating severely bleeding major trauma patients: a national study for England. Crit Care. 2015;19:276.
26. Li K, Xu Y. Citrate metabolism in blood transfusions and its relationship due to metabolic alkalosis and respiratory acidosis. International Journal of Clinical and Experimental Medicine. 2015; 8(4).
27. Pidcoke HF, McFaul SJ, Ramasubramanian AK, et al. Primary hemostatic capacity of whole blood: a comprehensive analysis of pathogen reduction and refrigeration effects over time. Transfusion. 2013;53 Suppl 1:137S-149S.
28. Jenkins D, Stubbs J, Williams S, et al. Implementation and Execution of Civilian Remote Damage Control Resuscitation Programs. Shock. 2014;41:84-89.
29.  Sprogøe U, Yazer MH, Rasmussen MH, Antonsen B, Bistrup C, Assing K. Minimal variation in anti-A and -B titers among healthy volunteers over time: Implications for the use of out-of-group blood components. J Trauma Acute Care Surg. 2017;82(Supp 1):S87-S90.
30. Berseus O. Effects on the anti-ABO titers of military blood donors from a predeployment vaccination program. J Trauma Acute Care Surg. 2017;82(6S Suppl 1):S91-S95.

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