Fibrinogen concentrate administration has been found efficacious at reducing transfusion requirements in trauma and surgical bleeding patients, when used as a first line therapy within a goal-directed coagulation management algorithm, based on point-of-care testing [8, 9, 14]. However, less is known regarding the utility of FBNc for controlling on-going haemorrhage and coagulopathy in non-trauma patients in whom a MTP has failed in improving the haemostasis and halting blood loss.
When assessed by adjusted analyses, our data showed that fibrinogen level upon admission was the only variable independently associated with both the global number of transfused units and the achievement of a target fibrinogen level of at least 2 g/L. Low and late dosage of FBNc (roughly 25 mg/kg) was found insufficient for attaining any of these endpoints. In agreement with published evidence on its high safety profile, even if administered at high doses (100 mg/kg) [1, 6, 8], no FBNc-associated thromboembolic event was observed.
As in other non-randomised studies [1, 3], we observed a non-adjusted significant decrement of the total number of transfused units after administering FBNc (N = 71 patients, within-group comparison) (Table 2). However, after adjusting, only the severity of illness, as assessed by SOFA, and low fibrinogen levels on admission, but not FBNc administration, were independently associated with blood component requirements (Table 3). Additionally, no differences in overall transfused units were observed after performing a paired-matched between-group comparison (Table 4).
Data on the use of massive transfusion protocols (MTP), outside of the trauma setting, are scant. The activation of MTP allows a faster and uniform issuing of blood products, though clinical outcome remains poor [16, 17], and early use of FFP to PRBC transfusion ratios of 1:1 or 1:2 ha become widespread , though the European guidelines for management of severe perioperative bleeding  do not provide precise recommendations either for plasma transfusion or for any specific plasma: RBC transfusion ratio. In contrast, these guidelines definitely recommend the use of predefined algorithms based on POC coagulations monitoring assays to guide haemostatic interventions aimed at improving outcome in elective surgery (1C) .
Regarding FBNc, with the exception of US guidelines, published guidelines suggest or recommend its administration in bleeding patients with either fibrinogen levels below 1.5 - 2.0 g/L or FIBTEM ROTEM evidence of functional fibrinogen deficiency [10–13, 18–20], despite this is not an approved indication for FBNc in all countries . Therefore, the risk to benefit balance of using FBNc as part of the MTP should be discussed at any institution.
We observed that both low fibrinogen levels on admission and maximum fibrinogen level within a 24-hours period after MTP activation were inversely and independently correlated with the number of transfused units (Figure 3): blood component transfusion increased by almost 3 units per each g/L decrease in admission fibrinogen level (Table 3). This is in agreement with the significant though weak-to-moderate correlation (R = -0.40) between pre- and postoperative fibrinogen levels and postoperative blood loss in cardiac surgery, found in a recent meta-analysis . However, FBNc administration did not reduce the use the allogeneic blood products in our patients (Table 3). More important, administration of low doses of FBNc was not associated with reaching an optimal fibrinogen level at least of 2 g/L. Several factors may have accounted for the apparent lack of efficacy of FBNc in this scenario.
First, these were bleeding patients (roughly one half undergoing cardiovascular or hepatic surgery) who had already received at least one massive transfusion package before administering FNBc. Our patient management protocol is opposed to that for patients included into a goal-directed therapy algorithm. For the later, two recent meta-analysis of 6 and 12 RCTs, respectively, demonstrated that administration of variable, goal-directed doses of FBNc effectively decreased transfusion requirements (6,15).
Second, the administered FBNc doses were at the lower range of guidelines’ recommendations . We administered 2 [1,6] g of FBNc reaching a post infusion fibrinogen level of 1.8 g/L. However, in 25% of patients, fibrinogen remained lower than 1.2 g/L within 12-hours following administration (Table 2). Moreover, for the whole sample (N = 141), only 53.8 % attained fibrinogen levels ≥2 g/L, despite massive transfusion, with or without the additional FBNc.
Higher doses (above 50 mg/kg) have been shown to reduce bleeding [6, 8, 9] and improve coagulopathy [22, 23]. Therefore, it is possible that FBNc doses were too low, resulting in inappropriate fibrinogen levels for improving haemostasis.
Third, independently of the threshold and target levels for FBNc administration, timing is also an important issue, which is not accounted for in current guidelines. In patients with massive haemorrhage, waiting for standard laboratory fibrinogen assessment invariably resulted in late FBNc administration . Even if FIBTEM ROTEM is used, a minimum running time will be needed (10–15 minutes), albeit significantly shorter than that for conventional laboratory .
We administered FBNc belatedly, when patients had already received 6 [5,9] units of blood components and had severe coagulopathy. Although speculative, it is conceivable that FBNc efficacy was sub-optimal because of late coagulopathy affecting platelets, proenzymes, and the fibrinolytic system . Earlier administration of coagulation factor concentrates might have resulted in improved treatment of coagulopathy and avoided the side effects of plasma administration .Lastly, a selection bias could have contributed to the apparent lack of efficacy of FBNc administration observed in our series. As depicted in Figure 1, clinicians were free for administering plasma, FBNc or both. In fact, FBNc was prescribed after transfusion of blood components had failed to correct coagulopathy and bleeding. Therefore, FBNc administration might actually be a surrogate marker of severity of illness.
Some limitations of our study should be acknowledged. First, its retrospective, uncontrolled nature does not allow an adequate estimation of the impact of FBNc therapy on transfusion requirements. However, adjusted analyses and matched comparison tried to overcome this bias. Second, blood transfusion is a surrogate marker of blood loss, and therefore changes in blood losses should have reflected better the efficacy of FBNc. Unfortunately, it was difficult to accurately measure the amount of blood loss. Third, patients who died within 24-hours from the onset of massive bleeding were excluded from the study. Lastly, we reviewed the FBNc efficacy at treating massive haemorrhage in non-trauma patients with heterogeneous diagnoses.
Despite the abovementioned limitations, our study has also important strengths. This is one of the few studies dealing with the use of FBNc, as a haemostatic intervention, in patients with severe perioperative bleeding managed with a MTP, and reporting on a relatively large sample of patients. Moreover, unlike most published studies, we performed multivariate analyses and used a comparator group to document FBNc efficacy.