Fibrinogen: the higher the better?

INTRODUCTION

Fibrinogen supplementation is currently indicated as therapy of severe bleeding in acquired fibrinogen deficiency. The recommended target fibrinogen level has evolved over the years from less than 1 g/L⁻¹, to 1.5 to 2 g/L⁻¹.^1–5 Some experts suggest even higher fibrinogen levels, such as 3 g/L and above^6,7. However, while these thresholds are based on appealing assumptions, they are not supported by clinical trials, expose patients to potential side effects and are costly. This commentary shows that lower thresholds are best practice.

PATHOPHYSIOLOGICAL RATIONAL FOR FIBRINOGEN SUPPLEMENTATION

There is a strong rationale for fibrinogen supplementation as low fibrinogen levels increase bleeding. Normal plasma fibrinogen concentrations range from 1.5 to 3.5 g/L⁻¹. Fibrinogen is critical for both primary and secondary hemostasis and clot formation. Cleaved by thrombin, it forms soluble fibrin monomers that polymerize to create a clot base and promote platelet aggregation by binding glycoprotein IIb/IIIa receptors on platelets. Fibrinogen depletion diminishes clot quality, characterized by increased fibrin network porosity and reduced clot stability against proteolysis with increased bleeding risk^2,8. Inherited afibrinogenemia is characterized by a severe bleeding phenotype. During severe bleeding, fibrinogen concentrations decrease due to blood loss, hemodilution, consumption and fibrinogenolysis. Fibrinogen is the first coagulation factor to reach critically low levels. Its decrease predicts bleeding severity, and low fibrinogen levels are associated with increased morbidity and mortality across various clinical contexts associated with severe bleeding^1–5.

Consequently, fibrinogen supplementation has been proposed during severe bleeding in order to restore properties of the clot and control bleeding. In vitro studies confirm that fibrinogen supplementation increases fibrin formation and network density in a concentration-dependent manner⁸. Moreover, increasing fibrinogen concentrations above the normal range results in further continuous improvement of mechanical properties of the whole blood clot⁹, leading to suggest higher fibrinogen thresholds for fibrinogen supplementation during bleeding. Nevertheless, to suggest is not to demonstrate.

POOR CLINICAL EVIDENCE SUPPORTING FIBRINOGEN SUPPLEMENTATION

Many randomized controlled trials (RCTs) have evaluated fibrinogen supplementation to control bleeding across various indications^10–15. Most were open-label and exposed to bias, but most failed to show an impact on clinically important outcomes, such as transfusion requirements, surgical reoperations, or mortality. In trauma, postpartum hemorrhage and liver surgery, all RCTs reported negative results despite administrated doses ranging from 1 to 6 g^10–14. In cardiovascular surgery, some trials demonstrated benefits. A meta-analysis of 8 RCTs by Li et al. found that fibrinogen concentrates reduced red blood cell transfusions but did not improve other clinically relevant or resource-related outcomes in cardiovascular surgery patients at high risk or with evidence of bleeding¹⁵. One explanation for repeated negative trials is that fibrinogen levels before fibrinogen administration were often within the normal range, sufficient to maintain clot function. The best illustration of this limitation is provided by two RCTs conducted by Meyer et al.: the first trial concluded that fibrinogen concentrate significantly reduced need for allogeneic blood transfusion in patients undergoing aortic surgery while the second trial failed to replicate these results^7,16. In the positive trial, the baseline fibrinogen concentration was 1.57 g/L⁻¹, whereas in the negative trial it was 1.9 g/L⁻¹, close to the upper recommended threshold. This difference may explain the negative outcome, supporting the argument against raising the fibrinogen supplementation threshold.

The question of increasing fibrinogen target levels is especially relevant in obstetrics, where fibrinogen levels are higher in pregnant women than in non-pregnant women. Fibrinogen concentrations gradually increase throughout pregnancy, peaking in the third trimester. There is also a strong association between early low fibrinogen concentrations and an increased risk of severe postpartum hemorrhage (PPH). Consequently, early fibrinogen supplementation has been proposed to maintain high concentrations, correct coagulopathy and improve maternal outcomes. However, a population-based cohort study including 730 women with severe PPH transfused with red blood cells during active bleeding found no improvement in maternal outcomes (number of transfused red blood cell units, maternal near-miss and death) with fibrinogen concentrate¹⁷. Additionally, all three RCTs evaluating fibrinogen supplementation during PPH yielded negative results^12–14. Interestingly, these trials tested high fibrinogen concentrations: mean fibrinogen concentrations after supplementation were were 3.2±0.9 g.L⁻¹, 4.2±0.8 g.L⁻¹ and higher than 4.5 g/L⁻¹ in the OBS2, FIDEL and FIB-PPH trials, respectively. Thus, there is no evidence to support increasing target fibrinogen levels above 2 g/L⁻¹ for managing severe PPH, as supraphysiologic fibrinogen levels do not reduce blood loss or transfusion requirements.

NO DATA FOR PROPHYLACTIC OR PREEMPTIVE FIBRINOGEN SUPPLEMENTATION

Similarly, preemptive administration of fibrinogen before bleeding, evaluated in RCTs in cardiac and non-cardiac surgery, has consistently failed to reduce transfusion requirements^18–20. Patients without hypofibrinogenemia at baseline did not benefit from supplementation, suggesting that fibrinogen concentrate is only effective in patients in cases of deficiency.

SAFETY CONCERNS ASSOCIATED WITH FIBRINOGEN SUPPLEMENTATION

Safety concerns include the potential association between increased fibrinogen concentrations, resulting from fibrinogen supplementation, and thrombotic events. Epidemiologic studies correlate long term hyperfibrinogenemia with arterial and venous thrombosis^21–22. Experimental models support a causative role for short-term hyperfibrinogenemia in thrombosis²¹. In vitro, elevated fibrinogen levels promote thrombus formation and stability via increased fibrin network density, mechanical strength and resistance to thrombolysis. In a murine model, fibrinogen infusion increasing fibrinogen concentration up to 4 g/L directly promoted thrombosis after vascular injury, with a dose-dependent effect²¹. Such results illustrate the risk associated with fibrinogen supplementation for supraphysiologic thresholds and suggest to monitor fibrinogen concentration and limit the amount of fibrinogen concentrates administrated. Clinical trials of fibrinogen use have been insufficiently powered to provide adequate assessment of safety outcomes, including thrombotic events. A meta-analysis by Gomes et al. concluded that fibrinogen concentrate did not increase total thromboembolic events compared with placebo in 6 RCTs including non-trauma and non-obstetric adult patients during perioperative care²³. However, these trials did not compare different fibrinogen levels, and the fibrinogen concentrate doses used did not significantly increase postoperative plasma fibrinogen concentrations. No study has been adequately designed to assess the thrombotic risk of fibrinogen supplementation while accounting for multiple potential causes of thrombosis in the complex setting of perioperative bleeding. In a randomised, placebo-controlled, double-blind trial by Bilecen et al., patients who underwent complex cardiac surgery and received fibrinogen concentrates targeting a fibrinogen level of 2.5 g/L⁻¹ showed no reduction in intraoperative blood loss compared to the placebo group but, according to the authors, experienced more myocardial infarctions and strokes, with 45% of these events occurring within the first 24 hours after surgery²⁴. This further supports avoiding higher fibrinogen targets.

FIBRINOGEN MONITORING

Fibrinogen monitoring is a key factor in deciding whether or not to supplement with fibrinogen and in choosing the right dose to avoid over-treatment. The most commonly used method for the determination of fibrinogen concentration is the Clauss method but the time required to obtain the results is a limiting factor, leading to blind supplementation based on clinical judgment when facing severe bleeding. Point-of-care viscoelastometric tests provide faster determination of the fibrinogen contribution to clot firmness than the Clauss method thus allow faster fibrinogen supplementation. Whatever the device (ROTEM, TEG or Quantra), viscoelastometric parameters assessing fibrin formation have good correlation with the Clauss fibrinogen assays, especially before bleeding treatment²⁵. Agreement between viscoelastometric parameters and the Clauss fibrinogen assay decreases considerably after fibrinogen administration, exposing to over-treatment²⁶. Moreover viscoelastometric tests have higher negative predictive values than positive ones for coagulation troubles, including fibrinogen deficiency, exposing also to unnecessary administration of fibrinogen²⁶. As an alternative to viscoelastometric tests, the development of rapid emergency hemorrhage panels on automated instruments in the laboratory allows rapid decisions on transfusion and fibrinogen supplementation in less than 20 minutes²⁷. These emergency panels, less expensive than viscoelastometric tests and easier to implement, may help to give the right dose of fibrinogen to the right patient.

Current international guidelines for bleeding management recommend considering the use of fibrinogen supplementation during excessive bleeding associated with hypofibrinogenemia, with target levels of 1.5–2 g/L⁻¹ (Table I)^1–5. They acknowledge that the evidence to support these target levels remains weak. Therefore there are no clinical data to justify raising the target levels. In addition, fibrinogen concentrates and cryoprecipitates are expensive and not universally available, further strengthening the argument against increasing fibrinogen doses. Fibrinogen supplementation for excessive bleeding is an ongoing area of research, and more data are needed to determine optimal administration practices and their impact on clinical outcomes.

Table I.

Target fibrinogen levels recommended for excessive bleeding by international guidelines

Society or expert group	Context	Recommendation
European Society of Anaesthesiology and Intensive Care (ESAIC) 1	Cardiovascular surgery	We recommend treatment with fibrinogen concentrate or cryoprecipitate if bleeding is accompanied by hypofibrinogenemia (viscoelastic signs of a functional fibrinogen deficit or a plasma Clauss fibrinogen level ≤1.5 g/L−1) (Grade 1B)
	Postpartum hemorrhage	Fibrinogen substitution in women with ongoing postpartum hemorrhage and a fibrinogen level above 2 g/L−1 or FIBTEM A5 >12 mm is not indicated (Grade 1B)
SSC on Perioperative and Critical Care Thrombosis and Haemostasis of the ISTH 2	Perioperative bleeding	We recommend against FC administration if the plasma fibrinogen concentration is over 1.5 g/L or if there is no evidence of functional fibrinogen deficiency on viscoelastic point-of-care analysis
Canadian National Advisory Committee for Blood and Blood Products 3	Postpartum hemorrhage	In a bleeding obstetrical patient with acquired hypofibrinogenemia, fibrinogen replacement is indicated when fibrinogen level is less than 2 g/L−1
	Perioperative bleeding	In a massively bleeding or preoperative patient with acquired hypofibrinogenemia, fibrinogen should be replaced when the level is less than 1.5 g/L−1
The Blood Conservation Working Group of the Society of Cardiovascular Anesthesiologists 4	Cardiovascular surgery	Treatment with fibrinogen concentrate may be considered for significant post-bypass bleeding with suspected or established fibrinogen deficiency (functional deficit by ROTEM/TEG or fibrinogen <1.5–2 g/L−1) although dosing and trigger/target values have not been determined
European Task Force for Advanced Bleeding Care in Trauma 5	Trauma patients	We recommend treatment with fibrinogen concentrate or cryoprecipitate if major bleeding is accompanied by hypofibrinogenemia (viscoelastic signs of a functional fibrinogen deficit or a plasma Clauss fibrinogen level ≤1.5 g/L−1) (Grade 1C)