Background

FFP is my trauma resuscitation fluid of choice, and for bleesing patients I try and get a couple of bags in before starting on the packed red cells. That’s not an especially evidence based approach, but there are signals in a range of trials that suggest that FFP has significant benefits for bleeding and head injured patients. However, FFP is expensive and difficult to store. It must be thawed, stored appropriately, and matched, which can delay delivery. Factor concentrates, on the other hand, are immediately available, pathogen reduced, and do not require group matching. In theory, they should provide a faster, simpler way to support coagulation at the bedside or even in remote environments. Early observational studies suggested they might reduce transfusion requirements, but clear, randomised evidence in trauma populations has been lacking.

In my air ambulance work I have access to FFP and blood, but when I am on for BASICS we do not have blood products and so it can sometimes feel limiting. There are other options such as freeze dried plasma, and these are used by some services,. especially in austere or military settings. The question is whether they are comparableto FFP?

The FiiRST-2 trial set out to test whether giving concentrates early, as a fixed-dose replacement strategy, would reduce the amount of blood products used in the first 24 hours compared with the conventional plasma-based approach. You can read the absrtact below, but as always please read the trial yourself and come to your own conclusions.

Abstract

Importance  Patients with bleeding and coagulopathic trauma often require more transfusions and have higher mortality rates, motivating research on improving hemostatic strategies.

Objective  To evaluate the replacement of clotting factors with frozen plasma (FP) or factor concentrates (fibrinogen concentrate [FC] and prothrombin complex concentrate [PCC]) in the initial resuscitation of patients with trauma.

Design, Setting, and Participants  This multicenter, parallel-control, superiority randomized clinical trial was conducted at 6 level I trauma centers in Canada, between April 2021 and February 2023. Eligible patients were those with massive hemorrhage protocol (MHP) activation on admission and aged 16 years or older. Patients were excluded if they received more than 2 red blood cell (RBC) units either before hospital admission or in the hospital prior to randomization or if they had a catastrophic head injury. Follow-up was completed on March 25, 2023. The primary analysis was based on the modified intention-to-treat approach.

Interventions  The intervention group received FC 4 g and PCC 2000 IU in MHP packs 1 and 2. The control group received 4 FP units. Concurrently, patients received 4 RBC units (both packs) and 1 dose of platelets (pack 2). After pack 2, FP was administered at clinician discretion.

Main Outcomes and Measures  Primary outcome was the number of allogeneic blood product (RBC, FP, and platelet) units administered within 24 hours. Secondary outcomes included incidence of thromboembolic events, duration of intensive care unit stay, and mortality.

Results  Of the 217 patients enrolled, 107 were randomly assigned to the FC-PCC group and 110 to the FP group; 137 patients were included in the primary analysis (66 in the FC-PCC group and 71 in the FP group). Baseline characteristics were similar between groups (median [IQR] age, 38 [29-55] years; 111 males [81.0%]). Among these patients, 95 (69.3%) had blunt mechanisms of injury, and the median (IQR) Injury Severity Score was 29 (19-43). Mean 24-hour transfusions were 20.8 (95% CI, 16.7-25.9) units in the FC-PCC group and 23.8 (95% CI, 19.2-29.4) units in the FP group. The mean ratio was 0.87 (1-sided 97.5% CI, 0.00-1.19; P = .20 for superiority). No significant differences were found in thromboembolic complications or 24-hour and 28-day mortality. The trial was terminated after the interim analysis showed conditional power of less than 25%, requiring an impractically large sample to show superiority.

Conclusions and Relevance  In this randomized clinical trial, clotting factor concentrates were not superior to FP for initial resuscitation of patients with trauma. Efficacy and safety outcomes were similar across the treatment groups.

What kind of study is this

This is a multicentre, superiority, parallel-group randomised controlled trial conducted across six Canadian level I trauma centres between April 2021 and February 2023. Patients were randomised to one of two arms as soon as an MHP was activated within an hour of hospital admission. The intervention group received a combination of fibrinogen concentrate (4 g) and prothrombin complex concentrate (2000 IU) in each of the first two MHP packs. The control group received frozen plasma, with four units included in each of the first two packs. Both groups also received four units of red blood cells with each pack, and platelets were added with the second pack. Tranexamic acid was administered to almost all patients, consistent with current best practice.

The design followed good clinical practice principles, with ethics approval, deferred consent procedures appropriate to the emergency setting, and oversight from an independent data and safety monitoring committee. A modified intention-to-treat analysis was used to account for the real-world issue that many patients have MHP activated but then stabilise before products are given (if this happened the patients were excluded from analysis).

The primary outcome was the total number of blood products transfused in the first 24 hours. Secondary outcomes included transfusion needs excluding the mandated products, the use of rescue haemostatic therapy, coagulation parameters, thromboembolic complications, ICU stay, ventilator-free days, and mortality at 24 hours and 28 days.

Tell me about the patients

From over five hundred patients who triggered MHP activation, just over two hundred were randomised. Of these, one hundred and thirty-seven ultimately received the allocated products and were included in the primary analysis. This attrition reflects the reality of MHP activation: many are triggered in error or stand down quickly when bleeding is controlled.

The included cohort was young, with a median age of 38 years, and predominantly male, reflecting the demographics of major trauma. Just under seventy per cent had blunt mechanisms of injury, and the median Injury Severity Score was 29, placing them firmly in the severely injured category. Around forty per cent arrived hypotensive with systolic blood pressure under 90 mmHg, and more than eighty per cent required at least three red cell units in the first hour, confirming that this was a genuinely bleeding population. Coagulopathy, defined by an INR greater than 1.2, was present in just over half of patients on arrival.

Most patients received tranexamic acid, consistent with modern protocols, and the time from injury to hospital admission was under an hour in both groups. This is an important contextual factor: Canadian trauma systems in urban centres often achieve rapid transfer, meaning the window from injury to haemostatic support was shorter than in some European trials.

What were the measured outcomes in this study

The trial’s primary outcome was the number of allogeneic blood product units (red cells, plasma, and platelets) transfused within the first 24 hours. This was chosen as a pragmatic measure of bleeding severity and treatment efficacy, acknowledging that transfusion burden is closely linked to outcomes but is not itself a direct patient-centred endpoint like survival.

Secondary outcomes included the number of blood product units transfused when the mandated initial interventions were excluded, the amount of rescue fibrinogen or PCC given later, and laboratory measures of coagulation. Clinically important endpoints included 24-hour and 28-day mortality, thromboembolic events, ICU and ventilator-free days, and complications such as abdominal or limb compartment syndrome. Safety was carefully assessed, with thromboembolic events adjudicated by blinded investigators.

What are the main results

The trial was stopped early after an interim analysis showed that the chance of demonstrating superiority with the planned sample size was below 25%. This means the results must be interpreted with caution.

• Primary outcome:
  • FC-PCC group: mean of 20.8 units transfused in 24 hours (95% CI 16.7–25.9).
  • FP group: mean of 23.8 units (95% CI 19.2–29.4).
  • The ratio was 0.87, but this did not reach statistical significance (p=0.20).
• Secondary outcomes:
  • When initial products were excluded, there was again no difference between groups (20.8 vs 19.1 units).
  • Rescue fibrinogen was required in far fewer patients in the FC-PCC group (26% vs 59%, p<0.001).
  • There was no difference in the need for rescue PCC.
• Mortality:
  • At 24 hours, mortality was 7.6% in the FC-PCC group and 16.9% in the FP group.
  • At 28 days, mortality was 13.6% vs 21.1%. Neither difference reached statistical significance.
• Safety:
  • Thromboembolic events occurred in 21% of FC-PCC patients and 14% of FP patients. This was not statistically significant, but the numerical difference will concern some clinicians.
  • There were no meaningful differences in ICU stay, ventilator-free days, or other major complications.

In summary, the concentrates did not reduce transfusion needs compared with plasma. However, mortality was less, but this diod not achieve statistical significance. The difference in death rates was largely attributed to early deaths within 24 hours.

How robust are the findings?

It’s good to see another randomised, multicentre, and pragmatic trial. The interventions were clearly defined, and compliance was high. The trial captured a genuinely sick population, with high injury severity and transfusion needs. So this is the sort of cases I see in Virchester both in and out of hospital.

The decision to use a modified intention-to-treat analysis was interesting given the frequency with which MHPs are activated in error or deactivated early. The modified aspect was that if patients were randomised, but thenb then decision to continue MHP was cxhanged befire it was started (whixch does happen) then they were excluded from the analysis. I think this is OK, but it’s not quite as robust and may have implications if the results are used in other settings (as decision points may change between clinicians). Safety monitoring and reporting were robust, and the study was transparent about industry involvement and funding.

But there are limitations. The most important is that the trial was stopped early, leaving it underpowered. With only one hundred and thirty-seven analysable patients, the study could not exclude clinically important differences in transfusion needs or mortality. This limits the strength of the conclusions. It’s also a bit disappointing to see that the trial primary outcome was blood product use, which is not really a patient centred outcome. I do prefer trials that look at mortality and function in the medium to long term. Mortality, or functional outcome, would arguably be more meaningful. The inclusion of patients with unsurvivable injuries may have diluted any potential effect of the interventions.

There were also challenges in group separation. Patients in the plasma arm could receive fibrinogen concentrate as rescue therapy if their levels were critically low, and indeed many did. This reduced the biological distinction between the groups and may have masked any true effect of the pre-emptive concentrate strategy.

The thromboembolic signal is worth attention. Although not statistically significant, the higher rate of events in the FC-PCC arm echoes concerns raised in the PROCOAG trial, which also found more thromboembolic complications in patients receiving PCC. While exposure-adjusted analysis mitigates this somewhat, safety cannot be ignored, and larger trials will be needed to clarify risk.

CRYOSTAT-2, which tested early high-dose cryoprecipitate, found no mortality benefit. PROCOAG, testing PCC alongside plasma, also found no benefit and raised safety concerns. RETIC, a smaller single-centre trial, suggested a benefit but is outweighed by the larger multicentre evidence base. Together, the current evidence suggests no clear superiority of factor concentrates over plasma in the early resuscitation of bleeding trauma patients.

Should we change practice based on this study

On the basis of FiiRST-2, alongside CRYOSTAT-2 and PROCOAG, there is no compelling evidence to replace plasma with fixed-dose factor concentrates in the early management of trauma haemorrhage. The standard plasma-based massive haemorrhage protocols remain evidence-supported and safe.

That does not mean concentrates have no place. Their logistical advantages are undeniable. In rural hospitals, military or prehospital environments where plasma is unavailable or impractical, they may provide the only realistic option. They also remain valuable in targeted use, such as documented hypofibrinogenaemia or warfarin reversal. But as a blanket replacement for plasma in trauma resuscitation, the evidence is not there.

Future research should focus on better patient selection, perhaps using predictive models or viscoelastic testing to identify those most likely to benefit. Trials should be powered for mortality and should pay close attention to thromboembolic safety. For now, though, clinicians should not change practice based on this study alone.

Summary

This trial tested whether giving fibrinogen concentrate and PCC instead of plasma in the first two MHP packs would reduce blood product use in severely injured trauma patients. The authors found no significant difference in transfusion requirements, mortality, or safety outcomes. The trial was stopped early for futility, leaving it underpowered and there may be a difference, but this trial cannot find it. That said, the findings align with other recent RCTs suggesting no superiority of concentrates over plasma.

So for now I am sticking with FFP as the plasma replacement of choice. I can see concentrates being used in selected circumstances or environments, but they should not yet replace plasma in routine trauma care.

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References

1. da Luz LT, da Silva V, Callum JL, Nathens AB, Pavenski K, Rizoli S, et al. Fibrinogen Concentrate Plus Prothrombin Complex Concentrate vs Plasma in Patients With Severe Trauma and Massive Hemorrhage: The FiiRST-2 Randomized Clinical Trial. JAMA Netw Open. 2025;8(9):e2531129.

2. Curry N, Stanworth SJ, Hopewell S, Doree C, Brohi K, Stanworth R, et al. The CRYOSTAT-2 trial: Randomized controlled trial of early cryoprecipitate in major trauma. Lancet Haematol. 2023;10(3):e173–e184.

3. Garrigue D, Godier A, Samain E, Hilly J, Raux M, Pons S, et al. Effect of Prothrombin Complex Concentrate on Blood Transfusion Requirements in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial. JAMA. 2023;329(8):661–670.

4. Innerhofer P, Fries D, Mittermayr M, Innerhofer N, von Langen D, Hell T, et al. Reversal of Trauma-Induced Coagulopathy Using First-Line Coagulation Factor Concentrates or Plasma (RETIC): A Randomized Clinical Trial. Br J Anaesth. 2017;118(6):834–844.

5. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023;27(1):311.

6. Shakur-Still H, Roberts I, Bautista R, Caballero J, Coats TJ, 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. 2010;376(9734):23–32.

7. Dan Horner, “CRYOSTAT-2 @ St Emlyns,” in St.Emlyn’s, October 18, 2023, https://www.stemlynsblog.org/cryostat-2-st-emlyns/.

8.  Simon Carley, “JC: Early plasma use in traumatic brain injury. St Emlyn’s,” in St.Emlyn’s, October 30, 2020, https://www.stemlynsblog.org/jc-early-plasma-use-in-traumatic-brain-injury-st-emlyns/.

9. Association of Prehospital Plasma With Survival in Patients With Traumatic Brain Injury https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563075/

10. Sperry JL, Guyette FX, Brown JB, et al. ; PAMPer Study Group . Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock https://pubmed.ncbi.nlm.nih.gov/30044935/

11. CRASH3 review on St Emlyn’s https://www.stemlynsblog.org/jc-tranexamic-acid-txa-in-head-injury-the-crash-3-results-st-emlyns/

12. CRASH-3. The Lancet. https://www.thelancet.com/. Published October 14, 2019. Accessed October 14, 2019

13. Natalie May, “JC: Blood Products in Trauma – What’s the Best (I)TACTIC?,” in St.Emlyn’s, October 22, 2020, https://www.stemlynsblog.org/jc-blood-products-in-trauma-whats-the-best-itactic/.

14. Dan Horner, “CRYOSTAT-2 @ St Emlyns,” in St.Emlyn’s, October 18, 2023, https://www.stemlynsblog.org/cryostat-2-st-emlyns/.

15. Simon Carley, “Top resuscitation papers for The Big Sick Conference 2024,” in St.Emlyn’s, February 7, 2024, https://www.stemlynsblog.org/top-resus-papers-for-tbs/.