Publication

• Title: 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
• Acronym: PROPPR (Pragmatic Randomized Optimal Platelet and Plasma Ratios)
• Year: 2015
• Journal published in: JAMA
• Citation: 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. doi:10.1001/jama.2015.12

Context & Rationale

• Background

  Early trauma deaths are frequently driven by uncontrolled hemorrhage and trauma-induced coagulopathy. Prior “damage control resuscitation” practice increasingly emphasized early, balanced component therapy (plasma + platelets + RBC) rather than RBC-heavy transfusion plus crystalloid, but much of the supportive evidence came from observational datasets vulnerable to survival bias and confounding.
• Research Question/Hypothesis

  Could a more hemostatic component strategy (1:1:1) meaningfully reduce early and/or overall mortality compared with a less plasma/platelet-intensive strategy (1:1:2), when delivered rapidly and in a protocolized fashion from the moment massive transfusion is initiated?

Design & Methods

• Research Question: In severely injured trauma patients predicted to require massive transfusion, does early transfusion in a 1:1:1 (plasma:platelets:RBC) ratio compared with a 1:1:2 ratio reduce mortality at 24 hours and/or 30 days?
• Study Type: Pragmatic, multicentre, randomized clinical trial at Level I trauma centers.
• Population: Highest-level trauma activations with active bleeding and predicted need for massive transfusion (enrolled at multiple U.S. Level I trauma centres; detailed operational workflow and trial conduct described in the design/implementation report).¹
• Intervention: Blood components delivered in a 1:1:1 ratio (plasma:platelets:RBC) as the initial empiric massive transfusion strategy.
• Comparison: Blood components delivered in a 1:1:2 ratio (plasma:platelets:RBC) as the initial empiric massive transfusion strategy.
• Blinding: Not blinded (product logistics make masking impractical). Primary endpoints are objective (all-cause mortality).
• Co-primary Endpoints: All-cause mortality at 24 hours and at 30 days.
• Statistics: Initial planned sample size 580 (powered for prespecified absolute differences), increased to 680 via adaptive design; primary analyses adjusted for site; critical p-value threshold adjusted for interim analyses (P ≤ 0.044).¹
• Follow-up: Primary endpoints at 24 hours and 30 days.

Key Results

This trial was not stopped early.

• Neither co-primary mortality endpoint reached statistical significance (24h: 12.7% vs 17.0%; 30d: 22.4% vs 26.1%).
• Hemorrhage-related death (exsanguination) within 24 hours was lower with 1:1:1 (9.2% vs 14.6%).
• More patients achieved hemostasis in the 1:1:1 group (86.1% vs 78.1%).
• The 1:1:1 strategy delivered more plasma (median 7 vs 5 units) and platelets (median 12 vs 6 units) during the first 24 hours, with similar RBC exposure (median 9 units).
• No meaningful differences were detected across prespecified complications, including ARDS and multiple organ failure.

Internal Validity

• Randomisation and allocation: Randomized assignment with a predefined blood bank delivery workflow designed to create rapid treatment separation early in resuscitation (a key methodological challenge for transfusion ratio trials).¹
• Performance/detection bias: Blinding was not feasible; however, both co-primary outcomes (24-hour and 30-day mortality) are objective and robust to ascertainment bias.
• Protocol adherence/treatment separation: A major threat in “ratio” trials is drift toward similar achieved ratios over time; PROPPR’s strength is earlier separation during the high-risk hemorrhage window, but later convergence and downstream care may dilute mortality differences.
• Missing data and multiplicity: Missing primary outcomes were rare (sensitivity analyses performed). Two co-primary endpoints and multiple secondary outcomes increase the risk of chance findings; interpretation appropriately centers on effect sizes, plausibility, and consistency (not only p values).
• Power and detectable effect: The trial was powered for relatively large absolute mortality differences; observed mortality differences were smaller, so “no statistically significant mortality benefit” should not be over-interpreted as “no clinically relevant effect,” particularly for early hemorrhage death.

Conclusion on Internal Validity: Internal validity is strong for the main question (mortality) because randomization was achieved and endpoints are objective; the main interpretive limitation is that the study was powered for large mortality effects and ratio separation may narrow beyond the earliest resuscitation period.

External Validity

• Population representativeness: Applies best to severely injured adults with active hemorrhage where clinicians initiate massive transfusion early (not to the broader trauma population).
• Setting requirements: The intervention assumes rapid access to thawed/liquid plasma and timely platelet delivery in the resuscitation bay—capabilities typical of high-resource trauma systems but variable globally.
• Applicability: Most applicable to centres using component therapy (rather than low-titer group O whole blood as first-line) and to protocols emphasizing immediate empiric component delivery before lab-guided refinement.

Conclusion on External Validity: Generalisability is high for mature Level I trauma centres capable of rapid component delivery, but implementation is constrained in systems with delayed plasma/platelet availability or different frontline products (e.g., whole blood).

Strengths & Limitations

• Strengths: Large multicentre randomised design; clinically meaningful co-primary endpoints; operationally realistic blood bank workflow; early delivery emphasis; important mechanistic/clinical secondary signals (hemostasis and hemorrhage death) without a detected increase in major complications.
• Limitations: Not blinded; inclusion based on predicted massive transfusion means some enrolled patients may not ultimately require large-volume transfusion (diluting effect); powered for large absolute mortality differences (smaller true effects could be missed); compares two “balanced” strategies rather than balanced vs markedly unbalanced care; does not directly answer ratio-based vs viscoelastic-guided or whole-blood-first strategies.

Interpretation & Why It Matters

• Mortality: “No difference” is not the whole story

  PROPPR did not show a statistically significant reduction in 24-hour or 30-day all-cause mortality with 1:1:1 versus 1:1:2. However, it demonstrated fewer deaths from exsanguination and higher rates of achieved hemostasis—signals that are biologically coherent with more hemostatic early resuscitation and clinically important given the time-sensitive nature of hemorrhagic death.
• Operational message: early balanced components

  The trial’s core contribution is pragmatic: it shows that in real trauma systems, early, protocol-driven delivery of balanced components is feasible and may reduce hemorrhage death without increasing major complications—supporting the continued use of empiric balanced transfusion at the front end of massive transfusion.
• Guideline-aligned practice

  Major trauma guidance commonly supports early empiric component therapy with plasma:RBC targets between ~1:1 and 1:2 (with platelet support), transitioning to lab/POCT-guided transfusion as bleeding control is achieved.³⁴

Controversies & Subsequent Evidence

• Observational “high-ratio” literature vs RCT effect size
  • Prior prospective observational work (e.g., PROMMTT) supported earlier and higher plasma/platelet delivery being associated with improved early survival, but observational studies are vulnerable to time-dependent survival bias (patients must live long enough to receive plasma/platelets).²
  • Meta-analyses often find lower mortality with higher plasma:RBC ratios, but results are heavily influenced by non-randomized data and heterogeneous definitions/timing of “ratio achievement.”⁵
  • Systematic reviews emphasizing randomized evidence conclude that certainty is lower than suggested by observational signals alone (and that effect estimates may be smaller and context-dependent).⁶
• Prehospital plasma: timing may matter as much as ratio
  • PAMPer (air medical prehospital plasma) reported lower mortality with prehospital plasma in patients at risk of hemorrhagic shock, while COMBAT (rapid urban ground transport) did not demonstrate a survival benefit—highlighting the importance of transport time and system context.⁷⁸
  • A harmonized post hoc analysis suggested benefit when transport times were longer (>20 minutes), reinforcing a “time-to-hemostatic-resuscitation” framework rather than a purely in-hospital ratio debate.⁹
• Empiric ratio-based vs goal-directed coagulation strategies
  • Whether empiric balanced transfusion should be augmented or replaced by goal-directed algorithms (e.g., VHA-guided therapy) remains debated; subsequent RCTs such as ITACTIC tested algorithmic, test-guided augmentation within major hemorrhage protocols, informing (but not definitively closing) this question.¹⁰
• Whole blood resurgence
  • Low-titer group O whole blood is increasingly used as a frontline product in some systems, conceptually approximating balanced resuscitation with simpler logistics; practice management guidance and meta-analyses exist, but much of the comparative evidence remains observational and heterogeneous.¹¹¹²

Summary

• PROPPR compared two protocolized, early component strategies: 1:1:1 vs 1:1:2 (plasma:platelets:RBC) in severely bleeding trauma patients.
• Co-primary mortality endpoints were not statistically different (24h: 12.7% vs 17.0%; 30d: 22.4% vs 26.1%).
• Clinically important secondary signals favored 1:1:1: fewer hemorrhage deaths (exsanguination) within 24 hours and more patients achieving hemostasis.
• No meaningful differences were detected in major complications (including ARDS and multiple organ failure), supporting safety of an early balanced approach.
• Contemporary trauma guidance broadly aligns with early empiric balanced transfusion (plasma:RBC between ~1:1 and 1:2, plus platelet support), transitioning to goal-directed strategies once bleeding slows and data are available.³⁴

Further Reading

Other Trials

• PAMPer Sperry JL, Guyette FX, Adams PW, et al. Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock. N Engl J Med. 2018;379:315–326. doi:10.1056/NEJMoa1802345
• COMBAT Moore HB, Moore EE, Chapman MP, et al. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet. 2018;392(10144):283–291. doi:10.1016/S0140-6736(18)31553-8
• ITACTIC Baksaas-Aasen K, Gall LS, Stensballe J, et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med. 2021;47:49–59. doi:10.1007/s00134-020-06266-1

Systematic Review & Meta Analysis

• 2018 Rahouma M, Kamel M, Jodeh D, et al. Does a balanced transfusion ratio of plasma to packed red blood cells improve outcomes in both trauma and surgical patients? A meta-analysis of randomized controlled trials and observational studies. Am J Surg. 2018;216(2):342–350. doi:10.1016/j.amjsurg.2017.08.045
• 2025 Brunskill SJ, Doree C, Stanworth S, et al. Blood transfusion strategies for major bleeding in trauma. Cochrane Database Syst Rev. Updated 2025. doi:10.1002/14651858.CD012635.pub2
• 2020 Crowe E, DeSantis SM, Bonnett CJ, et al. Whole blood transfusion versus component therapy in trauma resuscitation: A systematic review and meta-analysis. JACEP Open. 2020. doi:10.1002/emp2.12089

Observational Studies

• 1 Holcomb JB, del Junco DJ, Fox EE, et al; PROMMTT Study Group. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148(2):127–136. doi:10.1001/2013.jamasurg.387
• 2 Pusateri AE, Moore EE, Moore HB, et al. Association of Prehospital Plasma Transfusion With Survival in Trauma Patients With Hemorrhagic Shock When Transport Times Are Longer Than 20 Minutes: A Post Hoc Analysis of the PAMPer and COMBAT Clinical Trials. JAMA Surg. 2020;155(2):e195085. doi:10.1001/jamasurg.2019.5085

Notes

• “Ratio” evidence is highly time-dependent: patients must survive long enough to receive plasma and platelets, creating survival bias in observational analyses.
• PROPPR’s pragmatic contribution is early ratio separation during the highest-risk hemorrhage window; later convergence and downstream care can dilute mortality differences.
• Across trauma systems, the key implementation challenge is rapid availability of plasma and platelets (or alternative products like low-titer group O whole blood).

Guidelines

• ACS TQIP American College of Surgeons Trauma Quality Improvement Program (ACS TQIP). Massive Transfusion in Trauma Guidelines. Released October 2014.
• European Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023. doi:10.1186/s13054-023-04327-7
• EAST Meizoso JP, Moore EE, et al. Whole blood resuscitation for injured patients requiring transfusion: a systematic review, meta-analysis, and practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg. 2024. doi:10.1097/TA.0000000000004327

Overall Takeaway

In severely bleeding trauma patients predicted to require massive transfusion, PROPPR showed that a 1:1:1 component strategy did not significantly reduce 24-hour or 30-day all-cause mortality compared with 1:1:2, but it did increase hemostasis and reduce early deaths from exsanguination without a detectable increase in major complications. In practice, these findings support early, empiric balanced transfusion (often within plasma:RBC ranges of ~1:1 to 1:2 with platelet support), with transition to goal-directed strategies as bleeding control is achieved. ^{3 4}