Recombinant Activated Factor VII (rFVIIa, NovoSeven)

NovoSeven is approved in the United States for prophylaxis and treatment of hemorrhage in hemophiliacs with inhibitors of factor VIII, IX, or congenital factor VII deficiency. Despite its limited approval, it has been used off-label in patients with refractory traumatic hemorrhage. Although NovoSeven is extremely effective at stopping uncontrolled bleeding, it might not provide a survival benefit versus a placebo, as suggested by the CONTROL study. Moreover, there have been reports linking it to thromboembolic adverse events, such as an increased risk of stroke.

Four-Factor Prothrombin Complex Concentrate

Four-factor prothrombin complex concentrate (4F-PCC) contains plasma-derived, vitamin-dependent factors II, VII, IX, and X in their inactivated forms, as well as low amounts of the anticoagulant factors protein C, protein S, antithrombin III, and heparin. It has the advantages of requiring significantly less volume for infusion compared with plasma, achieving a more rapid reversal of the international normalized ratio (INR), and almost eliminating the risk of TRALI. PCC has US Food and Drug Administration (FDA) approval for the reversal of vitamin K antagonists, for example, warfarin, in patients with acute major bleeding, but has also shown promise in treating acute coagulopathy in trauma (off-label indication). In fact, its administration is recommended by European trauma guidelines in managing patients with evidence of delayed thrombin generation. Zeeshan and colleagues performed the largest retrospective analysis to date on the use of 4F-PCC in trauma. Their study suggests that 4F-PCC can be a useful adjustment to FFP for the control of posttrauma hemorrhage when used early.

Fibrinogen Concentrates

Fibrinogen is usually the first coagulation factor or protein to reach critically low levels in patients with trauma requiring MTP. Decreased fibrinogen levels in trauma are related to multiple factors, including blood loss, consumption of clotting factors and platelets, decreased fibrinogen synthesis due to hypothermia, dilution by fluids, and fibrinolysis. Fibrinogen concentrate is a pasteurized collection from human plasma that is FDA approved for the treatment of clinically significant bleeding in patients with congenital hypofibrinogenemia or dysfibrinogenemia, so its administration during trauma-related massive hemorrhage is considered off-label. Compared to FFP and cryoprecipitate, it has a minimal risk of infection transmission, the dosing is accurate and consistent, and it can be rapidly administered since it does not require thawing or crossmatching. A Cochrane Review by Wikkels⊘ et al found no differences in outcomes in terms of adverse events, bleeding, or recovery between fibrinogen concentrate and blood products. The bulk of studies that examine fibrinogen concentrate's role in trauma resuscitation are observational or retrospective cohort studies, and they do not offer strong evidence in favor of its use in severe trauma.

Tranexamic Acid

Tranexamic acid (TXA) is an antifibrinolytic that blocks the interaction of plasminogen with fibrin, effectively preventing clot breakdown and lysis. It can be used to treat hyperfibrinolysis in trauma, which is an independent predictor of mortality in patients with trauma. The CRASH-2 trial, an international randomized study of over 20,000 patients with trauma, found TXA was associated with a significant reduction in all-cause mortality compared with placebo (14.5% vs 16%, P = .035). Subsequent analyses revealed the greatest benefit of TXA was seen only when given less than 3 hours from injury, supporting early administration in trauma.

References

• Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69:489-500.
• Mengoli C, Franchini M, Marano G, et al. The use of fibrinogen concentrate for the management of trauma-related bleeding: a systematic review and meta-analysis. Blood Transfus. 2017;15:318-324.
• Napolitano LM, Cohen MJ, Cotton BA, et al. Tranexamic acid in trauma: how should we use it? J Trauma Acute Care Surg. 2013;74:1575-1586.
• Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.
• Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2); a randomized, placebo-controlled trial. Lancet. 2010;376:23-32.
• Wikkels⊘ A, Lunde J, Johansen M, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev. 2013;CD008864.
• Zeeshan M, Hamidi M, Feinstein AJ, et al. Four-factor prothrombin complex concentrate is associated with improved survival in trauma-related hemorrhage: A nationwide propensity-matched analysis. J Trauma Acute Care Surg. 2019;87:274-281.