First-Line Fibrinogen Concentrate for Bleeding Trauma

First-Line Administration of Fibrinogen Concentrate in the Bleeding Trauma Patient: Searching for Effective Dosages and Optimal Post-Treatment Levels Limiting Massive Transfusion - Further Results of the RETIC Study

Innerhofer N, Treichl B, Rugg C, Fries D, Mittermayr M, Hell T, et al. J Clin Med. 2021;10(17):3930.

• Fibrinogen supplementation is recommended for treatment of severe trauma haemorrhage
• Secondary endpoint analysis showed that response to fibrinogen concentrate (FC) supplementation and the dosage needed depend on baseline fibrinogen levels
• Post-treatment fibrinogen concentrations also predict the need for massive transfusion: individualising baseline dose may increase efficacy of first-line FC administration in limiting blood loss

Fibrinogen supplementation is recommended for treatment of severe trauma haemorrhage: it is needed for stable clot formation and bleeding cessation, and is the first coagulation factor to reach critical thresholds during ongoing bleeding¹.

The underlying evidence guiding the current European Guideline recommendations on fibrinogen supplementation dosing is low quality²

This analysis by Innerhofer and colleagues of a predefined secondary endpoint of the Reversal of Trauma-induced Coagulopathy using First-line Coagulation Factor Concentrates or Fresh-Frozen Plasma (RETIC) study provides additional data on how fibrinogen levels and fibrin polymerisation respond to first-line and rescue fibrinogen concentrate (FC) therapy. Primary endpoint results are published elsewhere^3,4.

The RETIC study was a single-centre, parallel-group, open-label, randomised trial in 100 acute trauma patients (Injury Severity Score >15) with clinical signs of or a risk for substantial haemorrhage and thromboelastometry-diagnosed poor fibrin polymerisation (FibA10 <9 mm) and/or prolonged initiation of coagulation (ExTEM CT >90 s). First-line therapy was standardised body weight-dependent coagulation factor concentrates (mainly FC, n = 50) or fresh frozen plasma (FFP, n = 44). Twenty-three patients received FC as rescue therapy when double-dose FFP failed to correct coagulopathy (complete data available for 20)³.

Figure 1. Change in fibrinogen concentration (FC) in patients successfully treated with (A) a single dose (SD) of FC (5 [4–5] g, n = 38, median change 83 mg/dL or (B) a double dose (DD) of FC (10 [8–10] g, n = 12, median change 197 mg/dL). Respective changes in Fib10A are also shown (C, median change 4 mm; D, median change 4.5 mm). Outliers are marked as °.

A single dose of FC (median 62.5 [57–66.66] mg/kg) normalised fibrinogen and/or FibA10 values in patients with baseline fibrinogen >100 mg/dL and/or FibA10 >5 mm (post-treatment: median fibrinogen 213 mg/dL, FibA10 11 mm). Patients with lower baseline fibrinogen/Fib10A needed a second dose of FC to achieve normal fibrinogen/FibA10 values (Figure 1).

Post-treatment fibrinogen/Fib10A levels could predict the need for massive transfusion (MT, ≥10 units packed red blood cells within 24 hours). Compared with 37.9% (11/29) of patients below a threshold of slightly over 200 mg/dL fibrinogen (Fib10A 14 mm), only 12.2% (5/41) of patients above it needed MT (OR 4.35 [1.1627–20], P=0.0194).

Finally, FibA10 values were shown to correspond well with FibA30 values and fibrinogen plasma concentrations, validating its use as an early marker for therapeutic decision-making.

Overall, these findings show that effective FC supplementation depends on baseline deficiency and early normalisation of fibrinogen levels, and they support the target of 150–200 mg/dL as recommended by most European Guidelines.⁵ Early correction of fibrinogen deficiency with FC could reduce the subsequent need for MT.

Individual dosing to increase efficacy of first-line FC

- The response to FC supplementation and the dosage required to normalise fibrinogen/FibA10 values were dependent on baseline fibrinogen levels

- As post-treatment fibrinogen concentrations also predict the need for MT, baseline-adapted individual dosing may increase the efficacy of first-line FC administration in limiting blood loss

References

1. Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg. 1995;81:360–365.q
2. Spahn DR, Bouillon B, Cerny V, Duranteau J, Filipescu D, Hunt BJ, et al. The European Guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019;23:98.
3. 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 Fresh Frozen Plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial. Lancet Haematol. 2017;4(6):e258–e271.
4. Tauber H, Innerhofer N, von Langen D, Ströhle M, Fries D, Mittermayr M, et al. Dynamics of platelet counts in major trauma: the impact of haemostatic resuscitation and effects of platelet transfusion - a sub-study of the randomized controlled RETIC trial. J Clin Med. 2020;9(8):2420.
5. Cěrný V, Maegele M, Agostini V, Fries D, Leal-Noval SR, Nardai G, et al. Variations and obstacles in the use of coagulation factor concentrates for major trauma bleeding across Europe: outcomes from a European Expert Meeting. Eur J Trauma Emerg Surg. 2021;1–12.