The most recent National Collection and Blood Utilization Survey, reporting data from 2011, noted US patients received 3.9 million plasma units that year. At 10 hospitals participating in the National Heart, Lung and Blood Institute sponsored Recipient Epidemiology and Donor Evaluation Study III (REDS III) program, at that time, patients received more than 72,000 plasma units or 1.9% of US plasma transfusions. Two units represented the median plasma transfusion dose with 39% of plasma infused as “thawed plasma.” (1) A survey of level I trauma centers, conducted in 2015, found 97% maintained thawed plasma inventories. (2) Once thawed, plasma has a 24 hour outdate, but can be relabeled “thawed plasma” with a 5-day shelf life if stored at refrigerated temperatures.
The REDS III investigators found no differences in INR responses to fresh frozen plasma versus thawed plasma after adjusting for pre-transfusion INR and plasma dose. (1) Thawed plasma provides inventory management advantages including rapid availability and reduced wastage since plasma is thawed prior to request and retains 5-days shelf life prior to expiry. In their discussion, REDS III clinicians questioned the use of plasma transfusions for INR levels less than 2.0 and the low plasma doses patients received.
In contrast, up to 25% of severely injured patients present with a coagulopathy at hospital admission. Almost 50% of trauma related fatalities occur within 24 hours of injury; 80% of intra-operative deaths are hemorrhage related. In response, multiple studies in military and civilian trauma situations demonstrate that massive transfusion protocols requiring multiple plasma, platelet, and red cell transfusions improve outcomes. Recent American College of Surgeons guidelines recommend immediate availability of plasma in the liquid state for balanced resuscitation (1:1:1 or 1:1:2 ratios of plasma, platelets, and red cells). Future accreditation standards will make this a requirement.
The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial randomized trauma patients to a 1:1:1 or 1:1:2 ratio, requiring the transfusion service to provide “universal donor plasma” in the liquid state, platelets, and red cells within 10 minutes of request. Experiences at the 12 level I trauma centers participating in the PROPPR trial demonstrated delivery of six units of plasma in the liquid state from group AB or group A donors within 10 minutes at 11 sites and within 15 minutes at the remaining institution. Sites met the 10 minute criteria by using thawed AB plasma, liquid plasma (i.e. never frozen plasma with a shelf life extending 5 days beyond the expiration time of donor derived whole blood when stored at 1 to 6 C— 26 days for blood collected with CPD anticoagulant preservative solutions), or anti-B low titer or not tittered group A plasma instead of AB plasma (in limited supply since only 4-5% of the population phenotypes as AB). (3)
Group A plasma in lieu of AB plasma as “universal donor” plasma takes advantage of a calculation showing 87% compatibility when un-typed recipients receive group A plasma; only group B and AB patients would receive incompatible plasma albeit with a high likelihood of low titer anti-A. In studies at the Mayo Clinic, the median anti-B titer was 1:16; 92% of donors had titers of 1:64 or less. (4) The Mayo Clinic implemented group A thawed plasma for emergency transfusions in 2008. They report a significant reduction in AB plasma use with no significant difference in adverse reactions in patients receiving incompatible group A plasma as a “universal donor” product as observed, similarly, in the PROPPR trial. (3,4) Among the level I trauma centers surveyed in 2015, 88% keep thawed group A plasma available and 69% use group A plasma for trauma patients for whom blood type information is not available; many implemented this strategy within the past year. (2)
With thawed plasma, losses occur in labile clotting factors and Protein S. Factor VIII declines significantly, falling to approximately 53-75% of baseline levels 5 days post-thawing with most of the decline occurring within the first 24 hours after thawing. Factor V levels drop to 70-86% of baseline and variable decreases occur in Protein S activity. Other Factor levels remain relatively constant although some studies show increased levels of Factors VII and XII, presumably related to cold or contact activation at refrigerated temperatures. (5) Factor XI increases, reported in some studies, correlates with venous thromboembolism in patients receiving immune globulin preparations, although this concern may not be relevant in bleeding patients. Indications for thawed plasma partially reflect these observations emphasizing its use for management of preoperative or bleeding patients, massive transfusions, and rapid reversal of warfarin therapy.
Recommendations for never frozen or liquid plasma, a product not readily available in the US at the current time but the subject of discussion, include massive transfusions in patients with life threatening hemorrhage. In one study, procoagulant and anticoagulant factor levels, determined on aliquots stored frozen and thawed immediately prior to testing, found retention of at least 50% activity for all factors after 15 days of storage, significant declines in Factors V, VII, VIII, vWF, and Protein S activity on day 15 compared to day 1, a significant reduction in thrombin generating capacity, and an increase in Factor VII activity after day 15. Those involved in this study, questioned whether liquid (never frozen) plasma stored for longer than 15 days was optimal, especially in light of significant depletion of Factor V and Protein S levels. (6)
Another study, assaying factor levels on freshly obtained aliquots that did not undergo freezing, found higher levels of platelet micro particles (which contribute to clot strength) in liquid plasma on day 26 of storage compared to day 0, more than 80% of initial factor levels on day 26 other than Factors V, VIII, and Protein S activity (the latter falling to 39%, 60%, and 29% of initial activity respectively). Thromboelastography studies found liquid, never frozen plasma had better clot forming capacity than thawed plasma. (7)
These three new approaches support adequate inventory maintenance and rapid plasma availability with reduced wastage for patients receiving massive transfusions—group A plasma as a supplement to group AB universal donor plasma, thawed plasma, and liquid or never frozen plasma. Available data encourage their usage with the expectation that additional clinical experience will provide greater perspective for optimizing and expanding their roles.
1. Triulzi D, Gottschall J, Murphy E, et al. A multicenter study of plasma use in the United States. Transfusion 2015;55:1313-1319.
2. Dunbar NM and Yazer MH. A possible new paradigm? A survey-based assessment of the use of thawed group A plasma for trauma resuscitation in the United States. Transfusion 2015; doi:10.1111/trf.13266
3. Novak DJ, Bai Y, Cooke RK, et al. Making thawed universal plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. Transfusion 2015;55:1331-39.
4. Stubbs JR, Zielinski MD, Berns KS, et al. How we provide thawed plasma for trauma patients. Transfusion 2015 doi:10.1111/trf.13156
5. Cardigan R and Green L. Thawed and liquid plasma-what do we know? Vox Sang 2015; 109:1-10.
6. Gosselin RC, Marshall C, Dwyre DM, et al. Coagulation profile of liquid-state plasma. Transfusion 2103;53: 579-90.
7. Matijevic N, Yao-Wei W, Cotton BA, et al. Better hemostatic profiles of never-frozen liquid plasma compared with thawed fresh frozen plasma. J Trauma Acute Care Surg 2012;74:84-91.