6. Massive Bleeding Protocols – The Transfusion Service Perspective

Key points:

• Definitions
• Rational for massive transfusion protocol and use of whole blood
• Background
• A suggested framework for massive transfusion protocol

Definitions

Historically, the definition of massive transfusion (MT) was defined as transfusion of ≥ 10 units of whole blood or packed blood cells (RBC) within 24 h, as an approximation of the replacement of ≥ 1 total blood volume (1). The definition of Dynamic MT is also summarized as transfusion of ≥ 4 units of RBC in 1 hour when ongoing need definitions for MT, including transfusion of ≥ 5 RBC units in 4h (2, 3), or ≥ 3 RBC units during any 1 h period in the first 24 h after hospital (4). A scoping review from Critical Care Medicine in 2023 concluded that the most commonly used definition for MT included transfusion of ≥ 10 units of RBC in 24 hours for completed trials, while for ongoing trials, a lower RBC volume over a shorter time period is being used to define MT. The definition still refers to RBC volume lost in 24 hours, not including other components. In the future, we believe it will refer to all components, to the whole amount of blood lost as new transfusion protocols recommend initiation transfusion with whole blood in the MT setting (5,6). Postpartum hemorrhage is defined as blood loss greater than 1000ml of blood and continuing to bleed (7). 

Why do we need a tool to manage massive transfusion?

Like any emergency and overwhelming situation in which a rapid response is in demand, preparedness of the blood bank with standard operating procedures and a massive transfusion protocol (MTP) enables an effective response and increases the chance to salvage patients. Major hemorrhage is associated with a high mortality rate, there are an estimated 30,000 yearly preventable civilian deaths in the USA secondary to hemorrhage caused by trauma, 25,000 of them in the prehospital phase of resuscitation and the remainder in-hospital (8). Trauma is associated with a high incidence of early trauma-induced coagulopathy which necessitates prompt management with appropriate blood component replacement (9). Practically the surgical team is concentrated on the mission of stopping the bleeding and the anesthesiology team is concentrated on keeping the patient oxygenated and perfused. One could compare the situation to an aviation team trying to land an aircraft safely under extreme weather conditions. The role of the blood bank team and the transfusion service consultant is similar to that of the air traffic control in an aviation emergency. We can proactively assist the team in the operation theatre or the Obstetric team in an event of massive bleeding. The blood bank and transfusion service can calculate how many blood components were transfused, examine the laboratory results and advise the treating team regarding recommended blood components. The MTP provides a framework for transfusing the patient effectively. 

Background

MTPs have been in use for approximately two decades. The US army recommended transfusion of plasma(FFP):(RBC) ratio 1:1 based on data from patients admitted to a combat support hospital in Iraq between 2003-2005 (10). The PROPPR trial, a large, randomized controlled trial conducted in traumatically injured patients with major bleeding, compared a ratio of 1:1:1 to 1:1:2 (FFP:PLT:RBC) and did not find significant differences in mortality at 24 h at 30 days, although there was reduced death from hemorrhage at 24 h (11). In the study by Baksass et al., patients were treated by empiric massive haemorrhage protocols (pRBC:plasma:platelets in a 1:1:1 ratio) and then randomised into viscoelastic or conventional coagulation testing-guided interventions. The viscoelastic testing group received higher early fibrinogen, with no overall difference in outcome (24 h after injury alive or free of MT). However, patients with traumatic brain injury demonstrated a reduced 28-day mortality in the viscoelastic testing group, a predefined secondary outcome (12). A review of the literature by Meneses et al. suggested use of a 1:1:1 or 1:1:2 ratio in adult trauma patients (13).

There is a European guideline for the management of major bleeding and coagulopathy following trauma, and the 6th edition was published in 2023 (14). According to this guideline a trauma center should have a local multidisciplinary, evidence-based treatment algorithm or clinical management guideline for the bleeding trauma patient, thus enabling cooperation and harmonized treatment. The algorithm should include initial resuscitation upon arrival of the patient to the hospital by administering blood components at a fixed ratio and the ongoing management of bleeding utilizing traditional laboratory testing and viscoelastic hemostatic assays (VHA) such as thromboelastography. 

Massive Transfusion Protocols

Table 1: Transfusion Packs Program (example), to be transfused after initial blood transfusion which composed of either LTOWB or RBC+FFP 

*In countries where cryoprecipitate is not available. RBC=packed red blood cells; FFP=fresh frozen plasma; RDP=random donor platelets; SDP=single donor apheresis platelets 

Coagulopathy induced by trauma and massive bleeding worsens the outcome of trauma patients and therefore should be minimalized (9, 20, 21). During rapid bleeding there is no time to wait for the laboratory test results to arrive (usually 45-60 minutes), because by the time they are released they may be irrelevant. For this reason, the protocol contains FFP upfront from the first pack and in all subsequent packs. The number of components in each pack is determined in each hospital according to the physical distance of the blood bank from the trauma bay and operating theater. When the distance is short, a smaller pack can be supplied, however, when the blood bank is not located in proximity to the trauma bay, larger packs should be used. 

Transfusion of low titer O whole blood (LTOWB) is becoming more prevalent in settings of massive bleeding, replacing the initial RBC+FFP transfused on arrival of the patient to the hospital. In a retrospective study of civilian trauma patients Seheult et al. concluded that LTOWB recipients had similar clinical outcomes compared to recipients of conventional component therapy (22). Concomitantly laboratory tests including complete blood count (CBC), prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen should be performed, as well as blood gas, Ph, lactate and base excess, viscoelastic hemostatic assays (VHA) such as thromboelastography. Once laboratory results are available, goal directed therapy can replace the fixed packs program. 
When the platelet count is less than 100X10³/μl, platelets should be given. If fibrinogen levels drop to less than 150 mg/dL, cryoprecipitate or fibrinogen concentrate 25mg/kg-50mg/kg 2-4 grams for adults of 80 kg should be administered (8,15). Cryoprecipitate is used more commonly in the USA, fibrinogen concentrate in Europe. Trauma is accompanied by fibrinolysis and tranexamic acid should be added during a time window of 4-6 hours from injury.  Its benefit was demonstrated both in trauma and in postpartum hemorrhage, and in both cases increased D-Dimers are observed (23,24,25).
When the patient is stabilized, the MTP can be terminated.

Post-Partum Hemorrhage

Postpartum hemorrhage is associated with a rapid decline of fibrinogen due to consumption. While the typical fibrinogen level in an adult male is 150-250 mg/dl, the level of fibrinogen in a woman in the third trimester of pregnancy is 400-600 mg/dl. Enhanced replacement of fibrinogen should be initiated from the first pack and augmentation of the dosage to 20 units of cryoprecipitate or 2-4 gm fibrinogen is common based on laboratory results. The use of fibrinogen concentrates instead of cryoprecipitate in post-partum hemorrhage is still being studied, to date rigorous studies comparing cryoprecipitate and fibrinogen concentrates in major obstetric hemorrhage are lacking (26).  A retrospective study by Myers et al. concluded that patients over 35 years with abnormal placentation at increased risk of requiring MT are eligible to receive LTOWB (27).  
Pediatric MTP is not discussed here, however blood banks should be prepared with a hospital protocol.

Summary

Appropriate upfront transfusion of LTOWB incorporated into MTPs is recommended in order to provide a balanced blood components supply in a short time. The components should be transfused according to the patient’s blood type as soon as possible in order to spare O units, especially in settings of multiple trauma patients. Since successful treatment depends on teamwork, transfusion specialists, medical directors of blood banks and the laboratory directors should be actively involved in planning institutional MTPs and they should be notified during an event of massive bleeding. 

References

1. Sihler KC, Napolitano LM. Massive transfusion: new insights. Chest. 2009;136(6):1654–1667. 
2. Mitra B, Cameron PA, Gruen RL, Mori A, Fitzgerald M, Street A. The definition of massive transfusion in trauma: a critical variable in examining evidence for resuscitation. Eur J Emerg Med. 2011;18(3):137–142. 
3. Zatta AJ, McQuilten ZK, Mitra B, Roxby DJ, Sinha R, Whitehead S, et al. Elucidating the clinical characteristics of patients captured using different definitions of massive transfusion. Vox Sang. 2014;107(1):60–70. 
4. Savage SA, Zarzaur BL, Croce MA, Fabian TC. Redefining massive transfusion when every second counts. J Trauma Acute Care Surg. 2013;74(2):396–400. 
5. Lin VS, Sun E, Yau S, Abeyakoon C, Seamer G, Bhopal S, et al. Definitions of massive transfusion in adults with critical bleeding: a systematic review. Crit Care. 2023 Jul 5;27(1):265. 
6. Green L, Tan J, Grist C, Kaur M, MacCallum P. Aetiology and outcome of massive transfusion in two large London teaching hospitals over a 3-year period (2012-2014) Transfus Med. 2017;27(Suppl 5):342–347.
7. Mavrides E, Allard S, Chandraharan E, Collins P, Green L, Hunt BJ, et al. on behalf of the Royal College of Obstetricians and Gynaecologists. Prevention and management of postpartum haemorrhage. BJOG 2016
8. Yazer MH, Cap AP, Spinella PC, Alarcon L, Triulzi DJ. How do I implement a whole blood program for massively bleeding patients? Transfusion. 2018 
9. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003
10. Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma - Inj Infect Crit Care. 2007
11. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, 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 - J Am Med Assoc. 2015
12. Baksaas-Aasen K, Gall LS, Stensballe J, Juffermans NP, Curry N, Maegele M, et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomised, controlled trial. Intensive Care Med. 2021
13. Meneses E, Boneva D, McKenney M, Elkbuli A. Massive transfusion protocol in adult trauma population. Am J Emerg Med. 2020
14. Rossaint R, Afshari A, Bouillon B, Cerny V, Cimpoesu D, Curry N, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023
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16. Schäfer N, Driessen A, Fröhlich M, Stürmer EK, Maegele M; TACTIC partners. Diversity in clinical management and protocols for the treatment of major bleeding trauma patients across European level I Trauma Centres. Scand J Trauma Resusc Emerg Med. 2015
17. Seheult JN, Bahr M, Anto V, Alarcon LH, Corcos A, Sperry JL, et al. Safety profile of uncrossmatched, cold-stored, low-titer, group O+ whole blood in civilian trauma patients. Transfusion. 2018
18. Torres CM, Kenzik KM, Saillant NN, et al. Timing to First Whole Blood Transfusion and Survival Following Severe Hemorrhage in Trauma Patients. JAMA Surg. 2024
19. Cotton BA, Gunter OL, Isbell J, Au BK, Robertson AM, Morris JA Jr, St Jacques P, Young PP. Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma. 2008
20. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma. 2003
21. Dann EJ, Michaelson M, Barzelay M, Hoffman R, Bonstein L. Transfusion medicine during the summer of 2006: lessons learned in northern Israel. Transfus Med Rev. 2008
22. Seheult JN, Anto V, Alarcon LH, Sperry JL, Triulzi DJ, Yazer MH. Clinical outcomes among low -titer group O whole blood recipients compared to recipients of conventional components in civilian trauma resuscitation. Transfusion. 2018
23. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet (London, England). 2010 Jul;376(9734):23–32.
24. Ducloy-Bouthors AS, Duhamel A, Kipnis E, Tournoys A, Prado-Dupont A, Elkalioubie A, et al. Postpartum haemorrhage related early increase in D-dimers is inhibited by tranexamic acid: haemostasis parameters of a randomized controlled open labelled trial. Br J Anaesth. 2016
25. Sentilhes L, Lasocki S, Ducloy-Bouthors AS, Deruelle P, Dreyfus M, Perrotin F, et al. Tranexamic acid for the prevention and treatment of postpartum haemorrhage. Br J Anaesth. 2015
26. O'Brien KL, Shainker SA, Lockhart EL. Transfusion Management of Obstetric Hemorrhage. Transfus Med Rev. 2018
27. Myers JC, Braverman MA, Ciaraglia A, Alkhateb R, Barry L, Brooke Z et al. Risk factors for massive transfusion in obstetrical hemorrhage and consideration of a whole blood program. Transfusion. 2023

Suggested Reading List:

References 8, 14  and 15.

The authors