Annual Meeting Reviews
Friday Session I: Transfusion
Reviewed by Michael Mulick, DO
Children’s Hospital Los Angeles
University of Southern California
Phillip C. Spinella, MD (Washington University) opened the meeting with an excellent talk and got right to the bottom line: whole blood is the wave of the future (and also the past). Fresh type O whole blood (4°C) can be stored for up to 15 days, can be available clinically, and is the optimal blood product for treating hemorrhagic shock. A 1:1:1 (plasma:platelet:RBC) ratio transfusion is the next best option. Dr. Spinella ran a level II trauma center in Baghdad, Iraq and had to deal with bleeding…a lot of bleeding. In this austere environment he and his colleagues were forced to approach transfusion differently. And combat victims are now surviving better than ever due to rapid access to tourniquets, intravenous adjuncts, and transfusion of warm whole blood.1,2 This was the birth of damage control principles for traumatic bleeding which then led to the evolution of massive transfusion protocols.1 The most important principle is that the practitioner needs to identify and rapidly treat trauma induced coagulopathy.1 In settings where resources are scarce, a program for walk-in blood donation that is rapidly available for transfusion works extremely well So well, in fact that the Royal Caribbean Cruise line has adopted and maintains competency in a whole blood transfusion program due to the lack of medical resources at sea. Over the last four years they improved mortality in severe GI bleeding in passengers. Dr. Spinella emphasized that if a cruise line can operate a fresh whole blood transfusion program on their many ships around the world, so too can any hospital.
For many decades the standard for transfusing for hemorrhage has been in ratios of far more blood than products. Was it always this way? If we glance back in time, we recall that whole blood was regularly transfused during the first two world wars. Sometime thereafter our attention was shifted towards treating coagulopathy in cancer patients. Blood constituents were split up and transfused separately and there has been resistance ever since to reconsider whole blood transfusions. Our most recent traditions of transfusion was based on first restoring cardiac output with crystalloid/colloid as well as packed red blood cells. However this approach failed to address the ensuing coagulopathy. It is now our understanding that we need a balanced approach that focuses on both coagulopathy and cardiac output. This is part of the rationale for whole blood transfusion. It is logistically simpler and more cost effective for the hospital and the patient. When compared side by side, the sum of the volumes of individual constituents is three times the volume of one whole blood unit. The sum of the constituents (1 PRBC + 1 PLT + 1 FFP + 1 CRYO) and their anticoagulants and additives add up to over a liter of volume with less anticoagulant property. Dr. Spinella suggests that it is time to learn about whole blood. It is US FDA approved and 15% of US children’s hospitals are currently using it. Furthermore, since it is FDA approved it is easy to study.
Ok, show me the data. In his retrospective study, Dr. Spinella found that warm fresh blood was independently associated with improved survival.2 In a different study comparing ratios, transfusion at lower plasma to RBC ratios were associated with higher mortality.3 These findings led up to the PROPPR randomized controlled trial where plasma, platelets, and RBC’s in ratios of 1:1:1 were compared to 1:1:2.4 Although there were no differences in the primary outcome of mortality, death due to exsanguination was significantly decreased in the 1:1:1 group.4
Dr. Spinella spoke briefly on the importance of intravenous hemostatic adjuncts. Recombinant FVIIa when used early with plasma transfusion was associated with higher 30 day survival rates.5 The caveat here is that they used it very early (within two hours of bleeding) and with fresh whole blood.5 The CRASH-2 trial was undertaken in 274 different hospitals and demonstrated that tranexamic acid reduced the risk of death in bleeding trauma patients.6
It is important to understand the concerns over whole blood transfusion and impediments to its widespread use. During combat conditions, the military did not conduct formal transmitted disease testing and thus transfused whole blood at 22°C. Since the general public uses whole blood stored at 4°C up to 21-35 days there is a concern that platelets are not functional at these sub-physiologic temperatures. Dr. Spinella presented a study by Manno et al published in 1991 where they prospectively looked at transfusion in children after cardiac surgery.7 The group that got cold whole blood had less bleeding in a 24 hour period.7 More interesting was that platelet aggregation was improved in the cold whole blood group compared to the 1:1:1 group where platelets were stored at room temperature.7 A randomized controlled trial in humans from 1973 showed cold platelets had better aggregation and faster correction of bleeding times than warm platelets.8 Another article in Transfusion 2013 compared cold whole blood to warm whole blood and showed retained hemostatic function of cold platelets up to 15 days. This has given encouragement to thinking that whole blood kept at 4°C could retain its hemostatic function up to 15 days.9 Warm platelets were only active up to 5 days.9 They also showed TEG data showing the maximum amplitude stayed high up to 15 vs. five days in cold and warm blood respectively.9 It is clear from this old and recent data that platelets have superior hemostatic efficacy at colder temps which is contrary to conventional teaching that platelets are not functional if they are stored cold. If platelets could be stored up to 15 days, this could increase a blood bank’s inventory three-fold.
There has been some concern that cold could irreversibly activate platelets and cause disseminated intravascular coagulation. This remains to be demonstrated. A group of investigators incubated cold platelets and found that cold platelets could be inhibited by nitric oxide and PGI2 which refutes the concept that cold induces irreversible activation.10
Another concern over the use of whole blood is whether it must be ABO specific. A consensus paper concluded that group O whole blood is preferred when ABO type cannot be confirmed.11 From analyzing data in the UK SHOT database, it was very clear that it was much safer to use whole blood when compared to type specific products.11 Whole blood had a mild to moderate risk of a non-fatal hemolytic transfusion reaction however this was only due to incompatible plasma.9 There was a not only a much higher chance of a transfusion reaction with type specific blood but that reaction was more likely to be fatal.11 And when low titer (IgM<1:100 or IgG <1:400) type O whole blood is used, the risk is even lower.11
The final criticism for whole blood is whether it can be leukocyte reduced and if it poses a risk for febrile reactions. This problem has been solved by using an FDA approved imuflex filter that is platelet sparing and currently being used by the Children’s Hospital of Philadelphia.
Dr. Spinella concluded his talk by stating that there are no clear indications or goals for administration of blood products and hemostatic adjuncts and assures us that this is just the beginning for whole blood. The Tactical combat casualty committee has concluded in 2014 that the number one fluid of choice for resuscitation of hemorrhagic shock is whole blood. The Department of Defense has also prioritized studying whole blood and the 2015 NHLBI State of the Science meeting platelet sub-committee prioritized the study of whole blood compared to components as well as the safety and efficacy of cold versus warm platelets for hemorrhagic shock. Therefore financial support of such future studies is anticipated. The pediatric community is encouraged to get involved in the large multi-center prospective trial already in place: the MATIC (Massive Transfusion in Children) study as more centers are needed. And finally Dr. Spinella invites us to learn more about opportunities for research on the THOR (Trauma Hemostasis Oxygenation Research Network) Network and the Pediatric Critical Care Blood Research Network (Blood Net).20,21
Nina A. Guzzetta, MD (Emory University School of Medicine) followed with her excellent talk on measuring and managing coagulation of trauma. The bottom line for her is that we have a tremendous opportunity to explore new technologies and research on measuring coagulation as well as how to create new transfusion protocols. She reminded us that 20% of trauma deaths are related to coagulopathy and that coagulopathy is independent of hemodilution and directly related to tissue hypoperfusion. Trauma induced coagulopathy (TIC) is an independent predictor of massive transfusion, protracted ICU stay, multi-organ failure, and death. In children, massive transfusion is the administration of greater than or equal to 1 blood volume in 24 hours, greater than or equal to 0.5 blood volume in 12 hours, or the acute administration of greater than or equal to 1.5 the estimated blood volume.12,13
In order to improve coagulation testing we need to understand the current limitations of the conventional tests. These tests are done on platelet poor plasma (PT, aPTT, INR). Platelet count and fibrinogen levels do not asses function. Conventional tests take a long time (45-75 minutes) and they are performed in plasma only. And finally these conventional tests represent a small proportion of the coagulation system where only 5% or less of prothrombin is converted to thrombin. There are point of care devices that can provide PT, aPTT, and ACT values but they generally do not correlate well with laboratory testing especially when the Hb level is low. Therefore we need to look at new ways to measure coagulopathy that can circumvent these issues.
Cohen et al showed that activated protein C had a significant positive correlation with aPTT, PT, tPA, and D-dimers and a negative correlation between FVa and FVIIIa.14 Furthermore there was a strong positive correlation of aPC and transfusion requirements and when aPC was activated there was increased risks of MODS, ALI, and mortality.14
Viscoelastic method such as TEG (thromboelastography) and ROTEM (Rotational Thromboelastometry) have the advantages of testing whole blood, being timelier, and being able to differentiate between a deficiency of coagulation factors, fibrinogen, and platelets and it can detect the presence of fibrinolysis. The image can be displayed on a screen in the operating theatre as the test is being run remotely. These tests can be run with modifications with different activators such as tissue factor only, intrinsic activators, individual platelet contribution, with platelet inhibition to see the fibrinogen component, and with the addition aprotinin to measure the degree of fibrinolysis. The maximum amount of thrombin generation can be derived from a TEG slope.
There is a growing body of evidence that these tests perform well in clinical situations and are useful in trauma patients. In a level I trauma center, ROTEM values were analyzed in 334 trauma patients and the ROTEM EXTEM was associated with early mortality.15 The rapid TEG was predictive of mortality and rapid TEG MA was predictive of life saving events (such as chest tube for hemothorax).16 Liras et al analyzed the trauma registry of the American College of Surgeons and found that hyperfibrinolysis on admission occurred more frequently in pediatrics (24%) than adults (9%).17 Mortality increased when the lysis at 30 minutes was greater than 3% and a greater than 30% lysis at 30 minutes was associated with a 100% mortality.17
Dr. Guzzetta presented contrary evidence about cold platelets where Wolberg et al published that platelet aggregation decreased when temperature dropped below 37°C.18 It’s important to understand how they measured this and that they discovered platelets did not bind Von Willebrand Factor as well in cold and adhere to the endothelial membrane.18 Furthermore there was altered enzymatic activity of all coagulation factors below 33°C.18 More clinical studies are obviously needed.
Dr. Guzzetta then described the different models to approach massive transfusion: component approach, predetermined blood product ratios, and TEG guided algorithms. Most of our research is based on the conventional tests (aPTT, INR, PT) and therefore there is still a role for them. INR and low platelet values have been helpful in predicting mortality. More recently the creation of massive transfusion protocols has attempted to lessen the hemodilution of coagulation proteins by infusion of crystalloid/colloid and RBC’s. The concept involved co-infusion of RBC:FFP:Platelets. As Dr. Spinella had also stated there is very little research on this in the pediatric population. We still want to know the optimal ratio.
TEG guided algorithms are intended to obtain a fast and accurate coagulation profile and provide goal directed resuscitation. This approach is best at determining slow clot formation and reduced clot strength and these tests have the advantage of detecting fibrinolysis. A study that compared TEG guided resuscitation vs. standard MTP showed that TEG guided therapy had improved early and 30 day mortality.19
Dr. Guzzetta spoke briefly about the problems of fresh frozen plasma. It is difficult to correct critical reductions in clotting factors with FFP because of its low concentration of clotting factors. The volume expanding effect of FFP counteracts the intended increase in clotting factors and the cooling of FFP to sub physiologic temperatures may alter clotting enzymatic activity. And thawing it causes delays in transfusion. Dr. Guzzetta spoke briefly on the important role of fibrinogen and prothrombin complex concentrate.
In summary, both talks were highly informative, relevant, and motivating. Although there was not an agreement on what cold temperature actually does to platelets, they both agreed that there can be variable results depending on how platelet function is measured. The panel ultimately stated that hemostatic adjuncts are useful and we need to conduct more research and to elucidate the best way to study coagulation, its methods of measurement, and to establish guidelines so that we can improve outcomes.
REFERENCES
- Spinella PC, Holcomb JB. Resuscitation and transfusion principles for traumatic hemorrhagic shock. Blood Reviews 23 (2009) 231-240
- Spinella PC et al. Warm fresh whole blood is independently associated with improved
survival for patients with combat-related traumatic injuries. J Trauma 2009;66:S69-S76 - Spinella PC et al. The ratios of blood products transfused affects mortality in patients
receiving massive transfusion at a combat support hospital. J Trauma 2007;63:805-813 - Holcomb et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs. 1:1:2 ratio
and mortality in patients with severe trauma. JAMA 2015;313(5):471-482. - Spinella PC et al. The effect of recombinant activated factor VII on mortality in combat-
related casualties with severe trauma and massive transfusion. J Trauma 2008;64:286-294 - Shakur H and CRASH-2 collaborators. Effects of tranexamic acid on death, vascular
occlusive events, and blood transfusion in trauma patients with significant hemorrhage
(CRASH-2): a randomised, placebo control trial. Lancet 2010;376:23-32 - Manno et al. Comparison of the hemostatic effects of fresh whole blood, stored whole
blood, and components after open heart surgery in children. Blood 1991;77:930-936 - Becker GA et al. Studies of platelets concentrates store at 22 C and 4 C. Transfusion
1973;13(2):61-8 - Pidcoke HF et al. Primary hemostatic capacity of whole blood: a comprehensive analysis of
pathogen reduction and refrigeration effects over time. Transfusion 2013;53(1):137S-149S - Reddoch KM et al. Refrigerated platelets respond to physiologic inhibitors, evidence that
cold-induced activation is unlikely to result in disseminated intravascular coagulation.
(unpublished) - Strandenes G et al. Low titer group O whole blood in emergency situations. Shock
2014;41(1): 70-75 - Handbook of Pediatric Transfusion Medicine 2004
- Hendrickson JE et al. Coagulopathy is prevalent and associated with adverse outcomes in
transfused pediatric trauma patients. J Pediatri 2012;160:204-9 - Cohen et al. Critical role of activated protein C in early coagulopathy and later organ failure,
infection, and death in trauma patients. Ann Surg 2012;255:379-85 - Tauber et al. Prevalence and impact of abnormal ROTEM assays in severe blunt trauma:
results of the “diagnosis and treatment of trauma-induced coagulopathy (DIA-TRE-TIC)
study. British J Anaesth 2011; 107: 378 - Vogel et al. Admission rapid thromboelastography delivers real-time “actionable” data in
pediatric trauma. J Pediatric Surg 2013; 48: 1371-6 - Liras IN et al. Prevalence and impact of admission hyperfibrinolysis in severely injured
pediatric trauma patients. Surgery 2015; 158(3):812-8 - Wolberg AS et al. A systematic evaluation of the effect of temperature on coagulation
enzyme activity and platelet function. J Trauma and Acute Care Surg 2004;56(6):1221-8 - Tapia NM et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in
massively transfused penetrating trauma patients. J Trauma and Acute Care Surg
2013;74(2): 378-86 - http://rdcr.org/
- http://www.bloodnetresearch.org/
