Severe traumatic injury is a major cause of morbidity and mortality, especially in young patients, and remains a major challenge for health care. The prognosis is significantly influenced by trauma-induced coagulopathy (TIC), which occurs in up to 25% of cases.1,2 TIC is classically associated with increased transfusion requirements and prolonged Intensive Care Unit (ICU) and hospital stay. Although there is no consensus on the definition of TIC, it is important to note that TIC is not limited to massive bleeding or hypoperfusion. Tissue damage caused by severe trauma and endothelial disruption activates the coagulation system through the release of tissue factor into the circulation, triggering a series of mechanisms leading to a state of early hypocoagulability.3

One of the mainstays of TIC is the depletion of fibrinogen, the clotting factor found in the highest concentration in plasma, with normal levels ranging from 200 to 400 mg/dl. Fibrinogen acts as an essential substrate for fibrin formation, promoting clot formation and stabilization, along with platelet aggregation and factor XIII. Mechanisms contributing to hypofibrinogenemia after major trauma include auto-consumption during coagulation, hypothermia, hypoperfusion, acidosis, as well as hyperfibrinolysis and dilution during resuscitation.4,5 Hypofibrinogenemia has been shown to be associated with increased adverse events, including increased mortality.6

Current recommendations suggest the administration of fibrinogen in situations of massive traumatic bleeding when levels fall below 150-200 mg/dl.7,8 However, classical coagulation methods can cause delays in determining these levels, and viscoelastic testing is not widely available in all centers. As traumatic injury is a time-dependent condition, the implementation of early or empiric hemostatic resuscitation strategies could improve clinical outcomes. In this context, the recent CRYOSTAT-29 trial evaluated the effect of early and empiric administration of cryoprecipitate in patients with severe trauma and hemorrhage, without demonstrating a significant reduction in mortality at 28 days.

In the setting of severe trauma, early recognition of the risk of developing hypofibrinogenemia is critical, especially considering the adverse effects of hypofibrinogenemia and the lack of consensus regarding empiric fibrinogen administration. Therefore, the present study aimed to develop an early predictive scale for hypofibrinogenemia in severe trauma to make its application practical, feasible, and effective.

During the study period, a total of 931 patients were admitted due to traumatic illness, of whom 754 were included in the analysis. The median age was 52 years (IQR: 37–67), and 74.4% were male. Most subjects presented with blunt trauma, and penetrating trauma was rare (3.4%). The median ISS and Retrascore were 22 (IQR: 16−27) and 4 (IQR: 2−7), respectively. Baseline patient characteristics are described in Tables 1 and 2.

The ICU mortality rate was 14.3% (108/754). Patients who died were significantly older and had greater severity according to the ISS (median 67 [IQR: 54−75] vs. 48 [IQR: 34−64] years; P < .001; median 26 [IQR: 25−38] vs. 20 [IQR: 16−25]; P < .001). The same group also had a higher incidence of hemorrhagic shock (32.4% vs. 13.6%; P < .001), traumatic cardiac arrest (19.4% vs. 1. 4%; P < .001), TIC (29.6% vs. 13.8%; P = .003), and acute renal dysfunction (37% vs. 10.5%; P < .001). Regarding the fibrinogen levels, deceased patients were more likely to have levels < 200 mg/dl (17.6% vs. 5.1%; P < .001) and <150 mg/dl (13.9% vs. 1.4%; P < .001). Cox regression showed a non-linear association between fibrinogen levels and ICU mortality. After adjustment for confounders, an inflection point was identified at 203 mg/dl, above which mortality increased significantly (hazard ratio: 1.66; 95%CI: 1.01–2.72; P = .046, Fig. 1). This threshold was used to define the presence of hypofibrinogenemia.

Figure 1.

Plot corresponding to the Cox regression analysis with restricted cubic splines.

There was a clear non-linear relationship between baseline fibrinogen levels and ICU mortality. From a critical threshold (fibrinogen 203 mg/dl, HR 1.66; 95%CI: 1.01–2.72; P = .046), mortality increased significantly with decreasing fibrinogen levels. The regression model was adjusted for age, the Injury Severity Score (ISS), initial vasopressor requirements, trauma-induced coagulopathy, acute renal dysfunction, need for transfusion > 2 packed red cell units, acidosis, the cranial Abbreviated Injury Scale (AIS), hypothermia, the Glasgow scale, traumatic cardiac arrest, initial hemoglobin < 10 g/dl and previous antiplatelet medication.

Table 3 describes the comparative characteristics between the hypofibrinogenemia and non-hypofibrinogenemia groups. The cohort with hypofibrinogenemia (≤203 mg/dl) had greater clinical severity, a higher incidence of extracranial hemorrhagic lesions, greater hemodynamic instability, and laboratory test data suggestive of tissue hypoxia. Multivariate analysis showed that the following variables were independently associated with the presence of hypofibrinogenemia (≤203 mg/dl): ionic calcium < 1.00 mmol/l (OR: 3.06; 95%CI: 1.70–5.47), hemoglobin < 10 g/dl (OR: 2.80; 95%CI: 1.56–5.01), platelet count < 100 × 109/l (OR: 2.25; 95%CI: 1.13–4.48), base excess < –6 (OR: 2.06; 95%CI: 1.09–3.86), SI > 0.9 (OR: 2.05; 95%CI: 1.06–3.97), and lactate > 2 mmol/l (OR: 2.04; 95%CI: 1.09–3.78), as shown in Fig. 2.

Figure 2.

Binary logistic regression constructed to identify factors independently associated with hypofibrinogenemia (≤203 mg/dl).

The predictors associated with hypofibrinogenemia were those surrogate markers of tissue hypoperfusion, both clinical (shock index) and laboratory (lactate, base excess, low hemoglobin), as well as those involved in hemostasis (platelet count and ionic calcium), whereas neither severity according to ISS nor any anatomical hemorrhagic lesion alone were found to be factors associated with hypofibrinogenemia.

iCalcium: ionic calcium; ISS: Injury Severity Score; TBI: traumatic brain injury.

In the overall cohort, the AUC-ROC of the FiT-6 scale was 0.86 (95%CI: 0.82–0.90). After cross-validation, FiT-6 retained high predictive ability in the validation cohort (AUC-ROC: 0.90; 95%CI: 0.86–0.94) (Fig. 3). In addition, internal validation was performed using bootstrap, which showed an optimism-adjusted AUC-ROC of 0.86, confirming the stability of the model and minimizing the risk of overfitting. The optimal cut-off for the detection of hypofibrinogenemia was ≥3 points, with a sensitivity of 78%, specificity of 81%, Youden index of 0.59, and accuracy of 81%. In the sensitivity analysis, the discrimination of the scale was evaluated for cut-offs ≤ 200 mg/dl and ≤150 mg/dl, with similar results (AUC-ROC: 0.86, sensitivity 77% and specificity 81%; AUC-ROC: 0.91, sensitivity 87% and specificity 77%). The sensitivity analysis specifically for blunt trauma (excluding penetrating trauma) showed that the FiT-6 scale had an AUC-ROC of 0.89, with an optimal cut-off point of 3 points - these results being very similar to those of the main analysis.

Figure 3.

Area under the ROC (receiver operating characteristic) curve of the FiT-6 scale in the validation cohort.

The shock index was considered in both prehospital and initial hospital care. The remaining predictors were those extracted during initial trauma care.

Secondary outcomes are summarized in Table 4. Patients with hypofibrinogenemia required more surgical procedures to control bleeding, received more blood product transfusions, and had a higher incidence of MODS and ARDS.

Our main finding was that the FiT-6 scale allowed early and appropriate identification of patients at high risk for hypofibrinogenemia in the setting of major trauma. A FiT-6 score of ≥3 points was associated with a high likelihood of fibrinogen levels ≤ 203 mg/dl, increased mortality, and greater transfusion requirements. Application of the scale in clinical practice could serve as an early warning to clinicians of the need for fibrinogen supplementation before critical levels are reached.

This study has made it possible to develop a predictive scale for early hypofibrinogenemia based on variables that are readily accessible from the first hospital contact. Some of these variables, such as base excess, lactate level, SI, and hemoglobin concentration, indirectly reflect the extent of hypoxia and tissue damage, phenomena closely related to accelerated fibrinogen consumption.12–15 In addition, interestingly, FiT-6 includes two variables not previously described as predictors of hypofibrinogenemia: platelet count and ionic calcium levels. The former is involved in fibrin-mediated platelet aggregation,16 while the latter acts as an essential cofactor in various phases of coagulation and can be reduced during hemostasis or by the effect of citrate on blood components.17 Both variables were found to be independently associated with early fibrinogen alterations, reinforcing their role in the pathophysiology of TIC. It is important to note that although FiT-6 was developed as a predictive scale for early hypofibrinogenemia, it does not directly predict hypofibrinogenemia per se, as this condition depends on multiple complex pathophysiological mechanisms beyond bleeding, such as hemodilution, accelerated consumption, fibrinolysis, hypothermia, acidosis, and endothelial dysfunction. Rather, FiT-6 identifies a clinical profile consistent with acute hemorrhage and tissue injury in which hypofibrinogenemia is significantly more likely to be present.

Previously, Gauss et al.18 proposed the FibAT scale to detect early hypofibrinogenemia (≤150 mg/dl) in patients with severe trauma. This scale is based on 8 variables (age < 33 years, heart rate > 100 bpm, systolic blood pressure < 100 mmHg, hemoglobin < 12 g/dl, hemoglobin delta > 2 g/dl, lactate > 2.5 mmol/l, temperature < 36 °C, and the presence of free intra-abdominal fluid). The authors considered a score of ≥5 to provide high specificity for the detection of hypofibrinogenemia, which could allow assessment of early initiation of treatment. Although FibAT is a valuable, timely, and well-constructed tool for the early detection of hypofibrinogenemia in severe trauma, it has some relevant differences from FiT-6 that may make the latter more efficient and applicable in our setting. First, FiT-6 requires only three positive variables to suggest early fibrinogen replacement compared to the five required by FibAT, making it more agile and feasible in high-pressure care scenarios. In addition, FiT-6 incorporates two key markers in the pathophysiology of traumatic coagulopathy (platelet count and ionic calcium levels) that are not considered in FibAT, giving it greater biological depth. Another important consideration relates to the FibAT criteria, such as age < 33 years, which could limit its sensitivity in populations such as ours, where the mean age of the patients was 57 years (the Spanish mean is close to 45 years), or the temperature cut-off of <36 °C, which could be considered somewhat permissive, including as hypothermic patients those individuals with temperatures above 35 °C, who would not normally be classified as hypothermic from a clinical point of view.

On the other hand, FiT-6 would have a strategic advantage if blood gas analyzers were available in the prehospital setting, since 5 of its 6 variables could be assessed at the actual trauma scene. This would make it possible to identify patients at high risk of hypofibrinogenemia before hospital admission, allowing early administration of fibrinogen before hospital arrival in cases where three or more criteria are present. This application would have great clinical potential and could be effectively integrated even in centers with viscoelastic testing, where FiT-6 would serve as an initial screening or therapeutic activation tool while viscoelastic test results are being processed. However, these strategies and the potential therapeutic impact of FiT-6 use in the prehospital setting should be validated by future prospective studies.19 It is also worth noting that even in the hospital setting, the FiT-6 scale could be useful in centers that do not have viscoelastic testing, since all its parameters can be obtained in a matter of minutes during initial care using a blood gas analyzer and an urgent blood count. This approach would make it possible to anticipate the need for fibrinogen replenishment more quickly than with conventional coagulation tests, which typically take considerably longer to provide results. An important aspect of the FiT-6 is its good diagnostic performance in detecting hypofibrinogenemia in patients with severe trauma. Its high NPV makes it a useful tool to rule out the disorder when the score is below 3, which can avoid unnecessary testing or treatment. In contrast, when the score is equal to 3, the PPV reaches 33.3%, meaning that one in three patients with this score has a hypofibrinogenemic profile. Although this value may seem limited, it represents a clinically relevant increase over the baseline prevalence (close to 11%) and could be sufficient to justify early administration of fibrinogen according to clinical judgment, especially in contexts of high suspicion. On the other hand, when FiT-6 is ≥4, the PPV increases significantly, which could provide even more robust support for early therapeutic decision-making in the initial management of major trauma.

The fibrinogen level at which replacement should be considered is still controversial. The European guidelines for massive bleeding recommend fibrinogen administration when levels are ≤150 mg/dl.7 However, the authors of these guidelines recognize that this cut-off represents a critical threshold, and in recent years, there has been an increasing tendency to initiate replacement therapy to achieve levels above 200 mg/dl. The HEMOMAS II document 8, which summarizes the Spanish recommendations for the management of massive bleeding, suggests considering the administration of fibrinogen when levels are below 150−200 mg/dl. This variability in proposed thresholds is partly explained by the fact that many studies have reported worse clinical outcomes in patients with severe trauma and levels ≤ 150 mg/dl20,21 as well as in patients with massive traumatic bleeding.22 Most of these publications define hypofibrinogenemia from critical levels, but other studies have found adverse associations even at levels below 200 mg/dl. Hagemo et al.,23 in a multicenter study of 1133 polytraumatized patients in several countries, identified an inflection point at 229 mg/dl, below which mortality at 28 days is significantly increased. In line with these findings, our study showed a similar nonlinear relationship with ICU mortality, setting the threshold for hypofibrinogenemia at 203 mg/dl. Both studies support the hypothesis that fibrinogen concentrations below this level are associated with a marked increase in mortality risk, reinforcing the need for early replacement strategies in patients with massive bleeding.

The effects of hypofibrinogenemia are not limited to cases of active bleeding. It has also been shown to be detrimental in patients with isolated traumatic brain injury (TBI). In a retrospective study by Lv et al.,24 of 2570 individuals with TBI, fibrinogen levels < 200 mg/dl at admission were independently associated with increased mortality at three months. In addition, the authors found that levels between 250 and 300 mg/dl correlated with better functional outcomes according to the Glasgow Outcome Score (GOS), further supporting the clinical relevance of fibrinogen as a prognostic biomarker even in the absence of massive hemorrhage. The clinical relevance of maintaining fibrinogen levels above 200 mg/dl has recently been supported by two clinical trials in neurotrauma. In one, Sabouri et al.25 found that administration of fibrinogen concentrate to maintain levels above this threshold in patients with severe TBI was associated with improved short-term neurological outcome and better control of hematoma expansion. Niakan et al.26 showed that correcting low fibrinogen levels (150−200 mg/dl) to >200 mg/dl in patients with severe TBI requiring neurosurgery resulted in a significant reduction in intraoperative bleeding. Taken together, these findings suggest that maintaining fibrinogen levels in the optimal range may help to optimize the prognosis of patients with TBI, both functionally and in terms of bleeding control. It should also be noted that in patients with TBI and concomitant hemorrhagic shock, the incidence of TIC can reach figures close to 60%, which is also associated with a significant increase in mortality. These data reinforce the need for early detection of alterations such as hypofibrinogenemia in particularly vulnerable patient subgroups, such as TBI with concomitant bleeding.27

This study has several limitations that should be considered when interpreting the results.

In effect, the retrospective nature of the analysis makes it susceptible to unobserved confounding factors that may have influenced the results or limited their applicability to other populations. However, a regression model adjusted for several relevant covariates in the trauma population was used, and a nonlinear regression analysis was performed that showed a progressive association between fibrinogen levels and mortality, making the results more robust than the simple definition of a cut-off point. Although some indication bias may exist because patients with hypofibrinogenemia received more harm reduction interventions, the actual impact on outcomes appears to be limited for two reasons. First, clinical severity was carefully adjusted for in the multivariate models, which reduces the risk of indication bias. Second, despite more intensive management, the hypofibrinogenemia group had higher mortality, suggesting that treatment was not a favorable confounder. Conversely, if such interventions had exerted a protective effect, it is reasonable to postulate that the association between hypofibrinogenemia and mortality might be underestimated rather than overestimated. Furthermore, the predictors included in the model (markers of tissue hypoxia, bleeding, and coagulopathy) have a robust pathophysiological basis that supports their clinical relevance.

On the other hand, although the FiT-6 scale has been developed and validated internally using cross-validation and bootstrap techniques, external validation is needed. It will be necessary to confirm the reproducibility and applicability of the scale in other cohorts of trauma patients. As the number of patients with hypofibrinogenemia was limited, a larger cohort may be required to strengthen the stability and generalizability of the model. External validation has already been considered as the next phase of the present project, to strengthen the robustness of the model and its clinical applicability.

In turn, in this study, fibrinogen levels were determined by the prothrombin time (PT) derived method, which is included in the standard panel of coagulation tests at hospital admission. Although the international reference is the Clauss method, in our center, it is reserved for cases with derived levels below 170 mg/dl, in line with the common practice of many national reference centers. It is important to note that the PT-derived method may overestimate the actual fibrinogen levels measured by the Clauss method, especially when these are low, as occurs in the context of coagulopathy, hypoperfusion, or massive hemorrhage. This overestimation may lead to an underestimation of the severity of hypofibrinogenemia, with possible clinical implications. However, the FiT-6 scale is not intended to predict absolute fibrinogen levels, but to identify a clinical profile compatible with a high risk of hypofibrinogenemia. Therefore, we believe that the utility of the tool is maintained even in contexts where the derived method is used. This methodological consideration is closely related to the need for external validation discussed in the previous limitation.

In turn, most of the cases in our cohort were blunt trauma, with a low representation of penetrating trauma, which could reduce the discriminatory capacity of the scale in this specific subgroup. However, penetrating trauma has a low incidence both in Spain and in Europe, with reported rates of around 4%; the distribution of our cohort is therefore consistent with that observed in other national and international registries of larger size, supporting the applicability of the analysis in our health care context.28 Finally, the therapeutic impact of the FiT-6 scale on clinical outcomes was not evaluated, which would require future prospective studies to validate its usefulness as a decision-making tool in the management of trauma patients.

In conclusion, the FiT-6 scale was developed and internally validated, being a simple clinical tool based on parameters accessible from admission, and which allows the early prediction of low fibrinogen levels - a condition associated with increased mortality and transfusion requirements. Its application could help in early therapeutic decision-making in severe traumatic disease, although our scale must be prospectively and externally validated to confirm its usefulness and clinical impact on patients.

ARB, GS, MC, SC, SU, XD, NM, JB, RA, MB, AR, and GM contributed to the conception, study design, data collection, analysis, and interpretation of the data. ARB, GS, MC, SC, SU, AR, MB, and GM participated in drafting the article and critical revision of its intellectual content. ARB, GS, MC, SC, SU, XD, NM, JB, RA, MB, AR, and GM contributed to the final approval of the version submitted.

The authors used ChatGPT-4 (OpenAI) as an assistive tool to improve the readability and clarity of the text under their supervision and responsibility.

None.