4F-PCC No Help in Trauma Patients at Risk of Massive Transfusion

Early administration of 4-factor prothrombin complex concentrate (4F-PCC) was of no benefit to patients with trauma at risk of massive transfusion, the randomized PROCOAG trial from France showed.

Among over 300 patients with the highest trauma level activation, the absolute difference in median total 24-hour blood product consumption between the 4F-PCC and placebo groups was 0.2 U (95% CI -2.99 to 3.33, P=0.72), reported Pierre Bouzat, MD, PhD, of Hôpital Albert Michallon in Grenoble, France, and co-authors.

Furthermore, 35% of patients in the 4F-PCC group presented with at least one thromboembolic event compared with 24% of the placebo group (relative risk 1.48, 95% CI 1.04-2.10, P=0.03), they noted in JAMA.

"Severe bleeding in patients with trauma remains a challenge," Bouzat and team wrote. "Use of tranexamic acid, reduction of fluid expansion, high-ratio blood product transfusion, and expedient hemorrhage control have improved some patient outcomes, but mortality among patients with trauma and bleeding remains high due in part to trauma-induced coagulopathy."

Previous observational studies have provided evidence that early administration of 4F-PCC to boost thrombin generation reduces blood product consumption, "but concern about a potential increase in thromboembolic events remains," they added.

In the current study, there were no between-group differences in secondary outcomes, including individual blood component units consumed within the first 24 hours, time to prothrombin time ratio (PTr) less than 1.5, time to hemorrhage control, 24-hour and 28-day mortality, number of intensive care unit-free days, ventilator-free days, and hospital-free days through day 28.

Our "findings do not support systematic 4F-PCC use in patients with trauma at risk of massive transfusion," the group concluded.

A post-hoc analysis of 266 patients looking at the association between coagulopathy and thromboembolic events showed a higher percentage of thromboembolic events in patients with a PTr greater than 1.2 who received 4F-PCC (34% vs 22% with placebo, P=0.06). In patients with a PTr less than 1.2, the percentage of those with thromboembolic events was the same between the 4F-PCC and placebo groups (33% vs 33%, P=0.99).

"The idea underlying the current trial's design was to generate a thrombin burst to reduce blood product use in patients with trauma at risk of massive transfusion," Bouzat and colleagues wrote. "However, trauma-induced coagulopathy is a complex hemostatic disorder, involving interactions between vessel wall, platelet, coagulation factor, and fibrinolysis factors."

"In response to tissue injury and shock, procoagulant factors levels decrease. In other consumptive coagulopathies, natural inhibitors of coagulation, such as antithrombin levels, are also decreased," they added. "This results in a new hemostatic balance and may explain why thrombin generation capacity is preserved despite PTr greater than 1.5 after trauma."

For this double-blind, placebo-controlled superiority trial, the researchers looked at 4,313 patients with the highest level of trauma activation admitted to 12 participating level I trauma centers in France from December 2017 through August 2021, and included 324 patients in their analysis -- 164 receiving 4F-PCC and 160 receiving placebo.

Median age was 39, and 73% were men. Median Injury Severity Score was 36, and median admission blood lactate level was 4.6 mmol/L. Prehospital systolic arterial blood pressure less than 90 mm Hg occurred in 59%.

All patients were at risk of massive transfusion, which was defined as administration of at least three packed red blood cell concentrates (PRBC) within the hour of admission or at least 10 PRBC within the first 24 hours.

Patients received intravenous administration of 1 mL/kg of 4F-PCC or 1 mL/kg of saline solution. All patients received early ratio-based transfusion and were treated according to European traumatic hemorrhage guidelines.

Bouzat and team noted that the study drug was administered in combination with fresh frozen plasma without prior viscoelastic testing, which may have exposed patients without coagulopathy to the risk of coagulation factor "overdosing," which was a limitation to the study.

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