Efficacy of prehospital administration of fibrinogen concentrate in trauma patients

Efficacy of prehospital administration of fibrinogen concentrate in trauma patients bleeding or presumed to bleed (FIinTIC)

A multicentre, double-blind, placebo-controlled, randomised pilot study

Ziegler B, Bachler M, Haberfellner H, Niederwanger C, Innerhofer P, Hell T, et al. Eur J Anaesthesiol. 2021;38(4):348-357.

Severely injured and bleeding patients can have trauma-induced coagulopathy (TIC), which increases patient mortality rate (Maegele et al., 2007). Therefore, any therapy that can improve blood clot stability in these patients may improve patient outcomes (Levy, et al., 2014). Fibrinogen is a critical factor in clot formation and falls to very low levels during severe bleeding (Levy, et al., 2014). European trauma guidelines recommend maintaining plasma fibrinogen levels above a certain value (Levy, et al., 2014; Spahn, et al., 2013).

In a recent prospective, international trial, Ziegler et al. (2021) used fibrinogen concentrate in the prehospital setting to improve blood clot stability in patients with trauma bleeding or presumed to bleed. The authors measured clot stability using the low- fibrin-based extrinsically activated test (FIBTEM) assay. Ziegler et al. (2021) showed that early administration of fibrinogen concentrate protects patients against early fibrinogen depletion, enhances quick blood clot initiation, and clot stability (Figure 1).

Figure 1. Study design and changes in FIBTEM^® MCF between baseline (T1) and 7 days post-trauma (T7) (adapted from Ziegler et al., 2021). ED, emergency department; FC, fibrinogen concentrate; MCF, maximum clot firmness; T, timepoint.

The study screened severely injured patients (≥18 years) with major bleeding, and a need for volume replacement therapy. The randomised schedule was stratified using a 1:1 ratio; the randomisation code was generated using the random permuted blocks method with varying block size (Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck). The drug dose was estimated by body weight to achieve the recommended dose of 50 mg/kg, and was administered intravenously at a rate of 20 ml/min. The primary endpoint was change in FIBTEM® maximum clot firmness (MCF) on arrival at the emergency department (ED) vs. the baseline. Secondary endpoints included the volume and requirements for transfusions within a week of starting the treatment, and ROTEM -assessed endpoints derived from the EXTEM, INTEM and APTEM assays^* to clot stability and time.

A significant change from baseline in FIBTEM MCF at T2 was observed between the two groups, with an increase in the fibrinogen concentrate group, but a decline in the placebo group (Group difference –5 (95% CI, -7 to –3); P<0.0001). The MCF also increased after FC treatment compared to placebo (Group difference –5 (95% CI, -8 to –2); P<0.0031), whereas the EXTEM clotting time decreased compared to placebo (Group difference 6.8 (95% CI, 0 to 12); P<0.0509). The evolution of FIBTEM MCF values over the 7-day study period was also higher in the fibrinogen concentrate than in the placebo group (across all timepoints) vs. placebo.

With regard to the secondary endpoints, no significant differences were observed in the study groups in 24-h volume therapy, transfusion requirements, or in the administration of coagulation factor concentrate. More colloid was observed in the group of patients treated with FC vs. placebo (2,475 vs. 1,000 ml; P=0.041), and tranexamic acid was administered less often to patients in the FC group (21.4%) compared to placebo (40%) (P=0.2304). Finally, results from the INTEM and APTEM assays were similar to those of the EXTEM and the FIBTEM.

Early administration of fibrinogen concentrate is clinically feasible during prehospital trauma care, even under busy and stressful emergency department conditions. Ziegler et al. (2021).

In summary, early treatment with fibrinogen concentrate in severely injured and bleeding patients can prevent early fibrinogen depletion, promote clot stability and rapid blood initiation. Although the primary endpoint is based on a non-clinical parameter, the results of this study are still clinically relevant.

Visit our learning zone on Fibrinogen Deficiency in Bleeding to find out more.

*The EXTEM assay is a screening test for the heamostasis system, the INTEM assay for the extrinsic haemostasis system and the APTEM assay is a modified EXTEM assay incorporating aprotinin to stabilise the clot against hyperfibrinolysis.

References

Jerrold H Levy, Ian Welsby, Lawrence T Goodnough. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion. 2014;54(5):1389-405.

Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D, Paffrath T, et al. Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury. 2007;38(3):298-304.

Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 2013;17:R76.

Wayne L, Chandler MD. Laboratory Techniques in Fibrinolysis Testing in Transfusion Medicine and Hemostasis (Third Edition), Elsevier Science 2019.

Ziegler B, Bachler M, Haberfellner H, Niederwanger C, Innerhofer P, Hell T, et al. Efficacy of prehospital administration of fibrinogen concentrate in trauma patients bleeding or presumed to bleed (FIinTIC). A multicentre, double-blind, placebo-controlled, randomised pilot study. Eur J Anaesthesiol. 2021;38(4):348-357.