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Foundational Trials

CRYOSTAT-2

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Publication

  • Title: Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial
  • Acronym: CRYOSTAT-2
  • Year: 2023
  • Journal published in: JAMA
  • Citation: Davenport R, Curry N, Fox EE, et al; CRYOSTAT-2 Investigators. Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial. JAMA. 2023;330(19):1882-1891.

Context & Rationale

  • Background
    • Severe traumatic haemorrhage remains a leading cause of early, potentially preventable death in major trauma systems.
    • Trauma-induced coagulopathy can develop rapidly; fibrinogen is often the first coagulation factor to fall to critically low concentrations, and hypofibrinogenaemia is associated with increased bleeding, transfusion requirements, and mortality.
    • Cryoprecipitate is a fibrinogen-rich blood component, but in many major haemorrhage protocols it is delivered relatively late because of product preparation/logistics and uncertainty about which patients benefit from empirical early replacement.
  • Research Question/Hypothesis
    • Whether empirical early high-dose cryoprecipitate, delivered within a pragmatic early window after injury, improves clinically meaningful outcomes (especially mortality) compared with contemporary standard care major haemorrhage protocols.
  • Why This Matters
    • “Front-loading” fibrinogen replacement would represent a major systems-level change (blood bank practice, transfusion packs, staffing, and cold-chain logistics).
    • If effective, early cryoprecipitate could reduce early deaths from bleeding and/or downstream organ failure; if ineffective (or harmful), it avoids unnecessary blood component exposure and resource use.

Design & Methods

  • Research Question: In adults with traumatic injury and active haemorrhage triggering a major haemorrhage protocol, does empirical early high-dose cryoprecipitate (in addition to standard care) reduce 28-day all-cause mortality compared with standard care alone?
  • Study Type: Pragmatic, parallel-group, randomised, multicentre, investigator-initiated clinical trial in 26 major trauma centres (UK and US); stratified by centre; open-label (no placebo).
  • Population:
    • Setting: emergency department / early in-hospital trauma resuscitation within established major haemorrhage protocols.
    • Inclusion: injured adults (≥16 years or judged adult), evidence of active haemorrhage with activation of a major haemorrhage protocol, systolic blood pressure <90 mm Hg at any time, and receipt of ≥1 unit of any blood component.
    • Timing: randomisation within 3 hours of injury.
    • Key exclusions: transfer from another hospital; >3 hours since injury; injuries considered incompatible with life (trauma team leader judgement).
  • Intervention:
    • Empirical high-dose cryoprecipitate: 3 pools (≈6 g fibrinogen equivalent) in addition to standard care.
    • Delivery goal: initiate as early as possible, targeting administration within 90 minutes of hospital arrival (and within 3 hours of injury).
    • Co-interventions: other resuscitation (RBC, plasma, platelets, tranexamic acid, procedures) per local protocol/clinician judgement.
  • Comparison:
    • Standard care major haemorrhage protocol (balanced component therapy as per site practice).
    • Cryoprecipitate permitted if/when triggered by local protocol and/or clinician judgement (i.e., not prohibited; typically later than the empirical early-dose strategy).
  • Blinding: Unblinded (no placebo cryoprecipitate); primary outcome (mortality) is objective, but transfusion decisions and some secondary outcomes could be influenced by knowledge of allocation.
  • Statistics: Sample size 1600 planned: powered to detect a 7% absolute reduction in 28-day mortality (from 26% to 19%) with 90% power at a 2-sided 5% significance level (group sequential O’Brien-Fleming design); primary analysis by intention-to-treat using mixed logistic regression adjusting for centre (with prespecified sensitivity analyses).
  • Follow-Up Period: Primary endpoint at 28 days; secondary follow-up included mortality to 6 and 12 months and functional/quality-of-life outcomes (including EQ-5D-5L and Glasgow Outcome Scale) at discharge and later follow-up.

Key Results

This trial was not stopped early. Recruitment proceeded to the planned sample size with a group sequential monitoring plan.

Outcome Early cryoprecipitate Standard care Effect p value / 95% CI Notes
All-cause mortality at 28 days (primary outcome; analysed population) 192/760 (25.3%) 201/771 (26.1%) OR 0.96 95% CI 0.75 to 1.23; P=0.74 Also reported: RR 0.97; 95% CI 0.81 to 1.17.
Mortality at 6 hours 56/784 (7.1%) 68/795 (8.6%) OR 0.82 95% CI 0.58 to 1.17; P=0.26 Absolute difference −1.4% (95% CI −4.1 to 1.2).
Mortality at 24 hours 88/783 (11.2%) 97/794 (12.2%) OR 0.91 95% CI 0.63 to 1.31; P=0.61 Absolute difference −1.0% (95% CI −4.2 to 2.2).
Kaplan–Meier estimated mortality at 12 months 26.6% (95% CI 23.6 to 30.0) 27.7% (95% CI 24.6 to 31.1) HR 0.96 95% CI 0.79 to 1.17; P=0.71 No long-term survival difference signal.
Cryoprecipitate pools transfused in first 24 hours (median [IQR]) 3 (3 to 3) 0 (0 to 2) Absolute difference 3 95% CI 3 to 3; P=Not reported Within 24 hours: 665/785 (85%) vs 256/795 (32%) received cryoprecipitate.
Total blood products in first 24 hours (units; median [IQR]) 12 (7 to 21) 10 (5 to 18) Absolute difference 2 95% CI 0.8 to 3.2; P=Not reported No meaningful difference in RBC or plasma units individually (medians 5 and 4 in both groups).
Crystalloids in first 24 hours (mL; median [IQR]) 2000 (700 to 3500) 1600 (250 to 3200) Absolute difference 400 mL 95% CI 131.5 to 668.5; P=Not reported Higher crystalloid volume in the early cryoprecipitate group.
Cumulative incidence of any thrombotic event at day 28 12.7% (95% CI 10.1 to 15.6) 12.9% (95% CI 10.2 to 15.8) Absolute difference −0.2% 95% CI −4.1 to 3.7; P=0.89 Venous thromboembolism: 6.9% vs 7.1%; arterial events: 3.3% vs 3.2%.
Ventilator days (median [IQR]) 1 (0 to 6) 1 (0 to 7) Absolute difference 0 95% CI −0.3 to 0.3; P=0.90 No detectable effect on ventilator utilisation.
EQ-5D-5L index value at discharge (median [IQR]) 0.51 (0.26 to 0.72) 0.50 (0.20 to 0.73) Absolute difference 0 95% CI −0.1 to 0.1; P=0.80 Patient-centred outcome at discharge unchanged.
  • Empirical early high-dose cryoprecipitate achieved earlier administration (median 68 minutes vs 120 minutes) and materially increased cryoprecipitate exposure (median 3 vs 0 pools in 24 hours), but did not reduce 28-day mortality.
  • There was no signal of benefit in early mortality (6-hour/24-hour), longer-term survival (12 months), or key downstream resource outcomes (ventilator days).
  • Prespecified subgroup: penetrating trauma had higher 28-day mortality with early cryoprecipitate (16.2% vs 10.0%; OR 1.74; 95% CI 1.20 to 2.51; P=0.006; interaction P=0.004), while blunt trauma showed no benefit (30.4% vs 34.8%; OR 0.82; 95% CI 0.62 to 1.09; P=0.16).

Internal Validity

  • Randomisation and allocation: centre-stratified computer-generated randomisation with sequential sealed envelope allocation; centre stratification and centre-adjusted modelling support balance, though envelope-based allocation can be more vulnerable to subversion than fully centralised randomisation.
  • Dropout/exclusions after randomisation: 1604 randomised (799 vs 805); 73 (4.6%) excluded from the primary analysis due to withdrawal of consent and/or primary outcome unavailable (39 vs 34), leaving 1531 analysed (760 vs 771).
  • Performance/detection bias: unblinded; transfusion escalation and adjunct haemostatic interventions could plausibly be influenced by knowledge of allocation; primary endpoint (death) is objective, but cause-specific death and thrombotic event ascertainment may be more vulnerable.
  • Protocol adherence: only 434/799 (54%) received the randomised intervention within prespecified delivery constraints (e.g., timing/dose criteria), with common deviations including administration >90 minutes and/or >3 hours from injury.
  • Timing and separation of the variable of interest: median admission-to-first cryoprecipitate 68 minutes vs 120 minutes (P<0.001); within 90 minutes, 68% vs 9% received cryoprecipitate.
  • Dose and separation of the variable of interest: cryoprecipitate pools in first 24 hours: 3 (3 to 3) vs 0 (0 to 2); total blood products: 12 (7 to 21) vs 10 (5 to 18).
  • Contamination/crossover: cryoprecipitate was administered within 24 hours in 256/795 (32%) of standard care patients (reflecting permissive standard care use), reducing the contrast to a “timing/threshold” strategy rather than “cryo vs no cryo”.
  • Baseline characteristics: broadly similar severity (ISS median 29 vs 29; SBP <90 mm Hg 32% vs 34%; tranexamic acid 79% vs 80%); notable imbalance towards more severe head injury in standard care (head AIS ≥4: 24% vs 29%).
  • Heterogeneity: 26 centres with inevitable variability in major haemorrhage packs, product delivery processes, and trauma case mix; centre stratification/adjustment mitigates (but cannot eliminate) heterogeneity in treatment delivery and co-interventions.
  • Outcome assessment: mortality endpoints are robust; functional outcomes (e.g., EQ-5D-5L, Glasgow Outcome Scale) require follow-up completeness and may be susceptible to missingness and response bias.
  • Statistical rigour: prespecified group sequential monitoring and modelling; 25 secondary outcomes without multiplicity adjustment raises false-positive risk for secondary/subgroup signals, especially when biological plausibility is uncertain.

Conclusion on Internal Validity: Overall, internal validity appears moderate: the randomised multicentre design and objective primary endpoint are strengths, but post-randomisation exclusions, incomplete delivery of the intended early-dose strategy, and contamination from standard care cryoprecipitate use plausibly bias effect estimates towards the null and complicate causal interpretation.

External Validity

  • Population representativeness: adults with severe traumatic haemorrhage requiring activation of a major haemorrhage protocol and hypotension (SBP <90 mm Hg), typical of high-risk trauma resuscitation cohorts in mature systems.
  • Case-mix: both blunt and penetrating injury were included; findings are most applicable to similar proportions of mechanisms and baseline mortality risk.
  • System dependencies: applicability is strongest for hospitals using component-based balanced transfusion and able to deliver cryoprecipitate within ~1–2 hours; external validity is reduced where cryoprecipitate is unavailable, slow to deliver, replaced by fibrinogen concentrate, or where prehospital whole blood strategies dominate.
  • Exclusions and boundaries: paediatric patients and inter-hospital transfers were excluded; findings should not be extrapolated to these groups without supportive data.

Conclusion on External Validity: Generalisability is moderate-to-good for major trauma centres with established major haemorrhage pathways; translation is more limited in systems with different blood component logistics, broader enrolment thresholds, or different fibrinogen replacement products/strategies.

Strengths & Limitations

  • Strengths: Large pragmatic multicentre randomised trial; clinically important primary endpoint; prespecified early delivery target; centre-stratified design with centre-adjusted modelling; broad capture of patient-centred and safety outcomes including longer-term mortality.
  • Limitations: Unblinded intervention; substantial deviation from intended early-dose delivery (54% received the intervention within prespecified delivery constraints); meaningful contamination with cryoprecipitate in the standard care group; post-randomisation exclusions due to consent withdrawal/missing primary outcome (4.6%); absence of selection based on measured fibrinogen deficiency may dilute benefit in patients without hypofibrinogenaemia.

Interpretation & Why It Matters

  • Clinical practice
    Empirical early high-dose cryoprecipitate, added to contemporary major haemorrhage protocols, should not be adopted as a universal default strategy for all eligible trauma activations given the absence of mortality benefit and increased blood component exposure.
  • Mechanistic implication
    The results support the concept that “earlier fibrinogen replacement” alone is insufficient in an unselected major haemorrhage population; benefit may require better patient selection (hypofibrinogenaemia/viscoelastic signal) and/or a product strategy that can be delivered reliably within very early windows.
  • Safety and heterogeneity
    Overall thrombotic event rates were similar, but the penetrating trauma subgroup signal (higher mortality) warrants attention when interpreting biological plausibility and planning confirmatory analyses.

Controversies & Subsequent Evidence

  • The accompanying editorial framed CRYOSTAT-2 as a rigorous test of a biologically plausible adjunct, but highlighted a recurrent trauma trial challenge: adjunct interventions often fail to translate into survival benefit when delivery is difficult to standardise in time-critical, heterogeneous haemorrhage care.1
  • Treatment fidelity was incomplete (54% received the randomised intervention within delivery constraints), and standard care contamination was substantial (32% received cryoprecipitate within 24 hours), meaning the intervention contrast functioned primarily as a timing/intensity shift rather than a binary exposure; this plausibly biases the trial towards a null effect for outcomes if “true early fibrinogen rescue” is the active mechanism.
  • The statistically significant interaction for injury mechanism (penetrating trauma) raises the possibility of genuine heterogeneity of treatment effect, but the interpretability is constrained by multiple subgroup testing and uncertain mechanistic plausibility; it is a hypothesis for confirmation rather than a practice-changing harm signal in isolation.
  • A subsequent systematic review and meta-analysis of early fibrinogen replacement strategies in traumatic haemorrhage (including cryoprecipitate and fibrinogen concentrate approaches) reported persistent uncertainty about mortality benefit and reinforced that timing, product selection, and patient selection remain central unanswered questions.2
  • Contemporary major bleeding guidance continues to recommend early assessment and replacement of fibrinogen when low (often via viscoelastic or laboratory measures) rather than universal empirical high-dose cryoprecipitate for all trauma haemorrhage activations, reflecting a shift towards targeted haemostatic resuscitation frameworks.345

Summary

  • In adults with traumatic injury and active haemorrhage triggering major haemorrhage protocols, empirical early high-dose cryoprecipitate did not reduce 28-day all-cause mortality compared with standard care.
  • The intervention achieved earlier cryoprecipitate delivery (median 68 vs 120 minutes) and higher cryoprecipitate exposure (median 3 vs 0 pools in 24 hours) but did not reduce RBC or plasma transfusion requirements.
  • Early mortality (6-hour/24-hour) and longer-term mortality (12 months) were similar between groups.
  • Thrombotic event rates and downstream resource outcomes (ventilator days, ICU/hospital utilisation, discharge quality of life) were not meaningfully different overall.
  • A prespecified injury-mechanism subgroup suggested higher mortality in penetrating trauma with early cryoprecipitate (interaction P=0.004), requiring cautious interpretation and confirmation.

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Guidelines

Notes

  • Guideline documents most relevant to trauma haemorrhage and fibrinogen replacement are largely from 2022–2023; no later guideline update explicitly focused on empirical early high-dose cryoprecipitate in trauma was available within the sources reviewed for this summary.
  • The “Systematic Review & Meta Analysis” list includes one trauma-specific systematic review/meta-analysis (2025) and additional high-level evidence syntheses and trials frequently cited in contemporary trauma haemostatic resuscitation discourse.

Overall Takeaway

CRYOSTAT-2 is a landmark pragmatic trauma transfusion trial because it tested a widely advocated, biologically plausible systems intervention—empirical early high-dose cryoprecipitate—at scale, across diverse major trauma centres, using an objective mortality endpoint. Despite demonstrable separation in cryoprecipitate exposure and earlier delivery, it did not improve survival, supporting a shift toward targeted fibrinogen replacement strategies rather than universal empirical administration during major haemorrhage protocols.

Overall Summary

  • Early high-dose cryoprecipitate increased fibrinogen-rich component exposure and occurred earlier, but did not reduce 28-day mortality in severe traumatic haemorrhage.
  • Overall safety signals (including thrombotic events) were similar, but a penetrating trauma subgroup showed higher mortality and should be treated as hypothesis-generating.
  • The dominant implementation lesson is that “early adjunct” trials must achieve reliable, near-universal early delivery and/or improved biological targeting to demonstrate benefit.

Bibliography