Blood loss and consumption of procoagulants during acute hemorrhage can reduce the plasma concentration of fibrinogen.1,2 Fibrinogen deficiency can develop earlier than other hemostatic abnormalities in the absence of plasma product transfusion.2 In this setting, hemostatic testing can inform coagulation management and clinical decision-making, particularly regarding the administration of fibrinogen-containing blood products.3 Clauss fibrinogen is a standard diagnostic tool but has limitations, primarily related to it being a laboratory-based assay.3,4 Viscoelastic testing (VET) using whole blood samples is recommended as a point-of-care alternative.3 The citrated multichannel (CM) cartridge for the TEG 6s hemostasis analyzer (Haemonetics Corporation) includes the citrated functional fibrinogen (CFF) assay, which assesses fibrinogen’s contribution to hemostasis.5 The TEG 6s citrated: K, KH, RTH, FFH (Global Hemostasis – HN) cartridge provides heparin neutralization capacity for the CFF assay (CFFH).5 This study aims to define clinical decision cutoff points for the maximum amplitude (MA) parameter of the CFFH assay, based on established Clauss fibrinogen assay cutoffs.
METHODS
This was a post hoc analysis of data from a prospective multicenter observational study conducted at 7 US centers (NCT06352125) that assessed the use of the TEG 6s HN cartridge in 335 patients undergoing cardiovascular surgeries/procedures or liver transplantation.6 The study was approved by a Western Institutional Review Board-Copernicus Group Institutional Review Board (IRB) (tracking number: 20212554) alongside site IRBs as per institutional policy. All participants provided written informed consent.
The present analysis used established Clauss fibrinogen cutoff points based on guidelines and manufacturer reference ranges (STA Clauss fibrinogen assay, STAGO): 150, 200, and 400 mg/dL, representing hypofibrinogenemia, low-normal fibrinogen, and hyperfibrinogenemia, respectively. Correlation of CFFH-MA and Clauss fibrinogen values was assessed by Spearman correlation. Receiver operating characteristic analysis was used to assess performance (sensitivity and specificity) of observed CFFH-MA values in the clinical trial population against the 3 fibrinogen cutoff values.
In addition, a transformation equation was developed to allow linear comparison of CFFH-MA measurements with the Clauss fibrinogen scale (mg/dL):
𝑍 = 13.01 × 𝑋 − 34.59,
where 𝑋 is CFFH-MA (mm) and 𝑍 is the transformed CFFH-MA (mg/dL).
Clinical decision cutoff points were then derived by back-transformation of CFFH-MA values in mg/dL to mm to estimate CFFH-MA cutoff points. Analyses were performed using R Statistical Software (v4.4.0; R Core Team 2024; R Foundation for Statistical Computing).
RESULTS
Patient characteristics are shown in the Table. Observed CFFH-MA measurements were positively correlated with Clauss fibrinogen (Spearman correlation: r = 0.75; 95% confidence interval, 0.72–0.78).
| Total | |
|---|---|
| Patients, n | 335a |
| Samples, n | 988 |
| Sex | |
| Female, n (%) | 143 (42.7) |
| Male, n (%) | 191 (57.0) |
| Age (y), mean (SD) | 60.16 (14.08) |
| BMI, mean (SD) | 28.71 (6.07) |
The Youden index (maximizing the sum of sensitivity and specificity) CFFH-MA cutoff points corresponding to Clauss fibrinogen values of 150, 200, and 400 mg/dL were 17.6, 19.5, and 25.1 mm, respectively. The specificity and sensitivity values were similar for the 3 CFFH-MA cutoffs (150 mg/dL specificity, sensitivity: 78%, 89%; 200 mg/dL specificity, sensitivity: 78%, 86%; 400 mg/dL specificity, sensitivity: 80%, 92%). The linear comparison/back-transformation analysis provided CFFH-MA cutoff values with specificity and sensitivity ranging between 87%–94% and 62%–72%, respectively.
Regarding the threshold commonly applied for fibrinogen supplementation, the Figure shows the range of CFFH-MA cutoff points for low-normal fibrinogen (Clauss fibrinogen level of 200 mg/dL) where sensitivity and specificity are both ≥0.7. A maximum specificity of 93% occurred at a CFFH-MA cutoff value of 17.0 mm (corresponding sensitivity =65%). A maximum sensitivity of 91% was observed where CFFH-MA was equal to 20.6 mm (corresponding specificity =65%). The cutoff point of equal sensitivity and specificity (82% for both) was at 19.1 mm. Equivalent sensitivity/specificity plots for the 150 and 400 mg/dL cutoff points are shown in Supplemental Digital Content, Figures S1 and S2, https://links.lww.com/AA/F314. Bland–Altman analysis showed good agreement between CFFH-MA and Clauss fibrinogen (Supplemental Digital Content, Figure S3, https://links.lww.com/AA/F314).
DISCUSSION
Fibrinogen deficiency is a significant concern during major surgery.2 Clauss fibrinogen has been considered the gold standard assay for assessing fibrinogen’s role in hemostasis,7 but it has limitations, including long turnaround, interassay variability, and lack of point-of-care functionality.3 The TEG 6s HN cartridge enables hemostatic assessment at the point of care while neutralizing the effects of heparin/heparin-like substances. This study defines and validates cutoff values for the TEG 6s CFFH assay for diagnosing hypofibrinogenemia, low-normal fibrinogen levels, and hyperfibrinogenemia versus Clauss fibrinogen. It also demonstrates close correlation between CFFH-MA values and fibrinogen levels measured by the Clauss method.
The consistently high sensitivity of the cutoffs aligns with the general understanding of VET performance. High sensitivity and robust specificity for hypofibrinogenemia suggests that the CFFH assay can accurately identify patients undergoing major surgery who need fibrinogen supplementation while confidently ruling out supplementation in those who do not require it. This balance could enhance patient safety and resource management, supporting effective patient blood management initiatives commonly associated with VET-based treatment algorithms.8 Sensitivity and specificity for the hyperfibrinogenemia cutoffs were similarly robust.
Our analysis suggests that clinical decision cutoffs for low-normal fibrinogen levels using the CFFH-MA parameter of the HN cartridge range between 17.0 and 20.6 mm, depending on whether sensitivity or specificity is prioritized. When maximizing the sum of sensitivity and specificity (ie, Youden index method), we identified a CFFH-MA cutoff value of 19.5 mm for low-normal fibrinogen (200 mg/dL), with a sensitivity of 86% and specificity of 78%. This value is comparable to a cutoff of 19.9 mm derived by Magunia et al. for CFF-MA (CM cartridge) after reversal of heparinization in a cardiovascular surgery population.9 Unlike the CM cartridge, the CFFH assay of the HN cartridge is designed to provide accurate measurements even under full heparinization, as shown by its performance in cardiopulmonary bypass (CPB) conditions with up to 5 IU/mL of unfractionated heparin.5 Thus, the HN cartridge offers a novel point-of-care tool for identifying hypofibrinogenemia earlier in cardiovascular surgery, before CPB weaning. Its utility could also extend to settings in which high levels of endogenous heparin-like substances can contribute to therapeutic hypocoagulability, such as liver transplantation.10
Overall, the clinical decision thresholds for the CFFH-MA assay presented here may expedite diagnosis and treatment of coagulopathy at the point of care. Prospective clinical studies are necessary to validate the integration of these cutoffs into treatment algorithms.
REFERENCES