Trauma-induced dysfibrinogenemia: the von Clauss assay does not accurately measure fibrinogen levels after injury

Abstract

Trauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion. This assay, however, infers fibrinogen levels optically via in vitro clot formation time and does not directly measure the quantity or quality of plasma fibrinogen. We hypothesized that the Clauss fibrinogen activity assay does not accurately reflect true fibrinogen levels in severely injured patients. Here, we demonstrate normal baseline plasma fibrinogen levels as measured by mass spectrometry despite coagulopathic Clauss values in severely injured patients. This discrepancy is most significant in patients with coagulopathy (international normalized ratio of >1.3) or with high shock, and persists even after fibrinogen repletion. These data highlight the need to reevaluate clinical testing of fibrinogen activity and transfusion criteria for the critically injured, and indicate that correcting shock and the oxidative, inflammatory milieu of trauma may be more effective at improving fibrinogen activity. This trial was registered at www.ClinicalTrials.gov as #NCT01838863.

Graphical abstract

Figure 1.

Trauma patient plasma collected out to 7 days after injury was analyzed by standard clinical assays and MS proteomics. (A) Patient baseline characteristics and demographics showing median (range) or proportion of specified variable. (B) Number of samples collected per time point. (C) Scatterplot of patients specified by tissue injury (NISS, x-axis) or shock (base excess [BE], y-axis) upon hospital arrival into shock-trauma (ST) groups of LSLT, LSHT, HSLT, or HSHT. Diamonds indicate death. BMI, body mass index; BPM, beats per minute; ICU, intensive care unit; SBP, systolic blood pressure; TBI, traumatic brain injury.

Figure 2.

Discrepancy between fibrinogen Clauss activity and MS level persists throughout acute and subacute severe injury. (A) Time series plot of Clauss fibrinogen activity displaying median activity ± IQR by ST group across time. Green is HC median level ± IQR. (B) Time series plot of MS fibrinogen levels displaying median levels ± IQR by ST group across time. Green is HC median level ± IQR. (C-F) Clauss fibrinogen activity and MS fibrinogen levels at ED and hour 6 after injury by ST group. Significance determined as ∗∗P < .005, ∗∗∗∗P < .0005 by Kruskal-Wallis test.

Figure 3.

Clauss activity and MS fibrinogen levels correlate poorly with coagulopathy (Coag.), shock, and tissue injury. (A) Scatterplot of Spearman rho correlation values by P value for patients with/without coagulopathy, shock, or tissue injury, and (B) Spearman rho correlation and P values for associated groups. (C-H) Box plot comparisons of Clauss fibrinogen activity and MS fibrinogen levels by (C-D) tissue injury, (E-F) shock, and (G-H) coagulopathy upon ED arrival. Significance determined as ∗P < .05, ∗∗∗∗P < .005 by Wilcoxon signed-rank test.

Figure 4.

Fibrinogen supplementation increases MS fibrinogen levels but does not increase Clauss activity. (A) Percent change from ED to 6 hours after injury of (A) Clauss activity after cryoprecipitate transfusion, (B) MS fibrinogen levels after cryoprecipitate transfusion, (C) Clauss activity after platelet transfusion, and (D) MS fibrinogen levels after platelet transfusion.