How is fibrinogen supplementation managed in critical care situations with low fibrinogen levels?

Fibrinogen Supplementation in Critical Care

Treatment with fibrinogen concentrate or cryoprecipitate is recommended when major bleeding is accompanied by hypofibrinogenemia (viscoelastic signs of functional fibrinogen deficit or plasma fibrinogen level ≤1.5 g/L). 1

Fibrinogen's Critical Role in Hemostasis

• Fibrinogen is the most abundant coagulation factor in blood with normal plasma concentrations ranging from 2.0-4.0 g/L 2
• During major hemorrhage, fibrinogen is the first coagulation factor to reach critically low levels (<1.0 g/L) due to consumption, dilution, and hyperfibrinolysis 2, 3
• Low fibrinogen levels significantly impair fibrin clot strength and are associated with increased bleeding risk 2, 4
• In trauma patients, decreased fibrinogen concentration predicts hemorrhage severity 2

Monitoring Fibrinogen Levels

• Repeated measurements of plasma fibrinogen concentration are strongly recommended in critically ill patients with major bleeding 4
• Fibrinogen measurement is typically performed using the Clauss method, with a reference range of 1.8-3.5 g/L 2
• Viscoelastic testing methods (thromboelastometry/ROTEM or thromboelastography/TEG) can provide rapid assessment of functional fibrinogen status 5, 6
• In trauma patients, a maximum clot firmness (MCF) of 7 mm using thromboelastometry corresponds to a fibrinogen level of approximately 2 g/L 2

Fibrinogen Replacement Strategies

Recommended Thresholds for Replacement

• Current guidelines recommend maintaining plasma fibrinogen levels above 1.5 g/L in coagulopathic patients with significant bleeding 1
• Treatment should be initiated when:
  • Viscoelastic testing shows signs of functional fibrinogen deficit 1
  • Plasma Clauss fibrinogen level is ≤1.5 g/L 1

Dosing Recommendations

• An initial fibrinogen supplementation of 3-4 g is recommended 1
• This is equivalent to 15-20 single donor units of cryoprecipitate or 3-4 g fibrinogen concentrate 1
• Repeat doses should be guided by viscoelastic monitoring and laboratory assessment of fibrinogen levels 1

Available Products for Fibrinogen Replacement

1. Fibrinogen Concentrate:

   • Provides a standardized dose of fibrinogen in a small volume 3
   • Can be rapidly administered with minimal preparation time 7
   • Virally inactivated as standard 3
   • Shows less variability in fibrinogen concentration compared to cryoprecipitate 7

2. Cryoprecipitate:

   • Plasma-derived product rich in von Willebrand factor (VWF), fibrinogen, and fibronectin 1
   • Requires thawing before administration, causing potential delays 7
   • Shows higher variance in fibrinogen content compared to concentrates 7

3. Fresh Frozen Plasma (FFP):

   • Contains all coagulation factors but at lower concentrations 3
   • Requires larger volumes to achieve adequate fibrinogen levels 3
   • Associated with higher risk of transfusion-related complications 6

Clinical Evidence and Recommendations by Setting

Trauma

• The European guideline on management of major bleeding following trauma (2023) recommends treatment with fibrinogen concentrate or cryoprecipitate when major bleeding is accompanied by hypofibrinogenemia 1
• Early fibrinogen supplementation has been associated with improved outcomes in trauma patients 4
• Viscoelastic testing can guide individualized goal-directed fibrinogen therapy in traumatic coagulopathy 1

Critical Care

• The European Society of Intensive Care Medicine (2021) makes no recommendation regarding early empiric fibrinogen replacement in critically ill patients with massive hemorrhage due to trauma, citing low certainty evidence 1
• However, they acknowledge that fibrinogen may reduce transfusion needs in patients with low fibrinogen levels 1

Cirrhosis and Liver Disease

• In cirrhosis, plasma fibrinogen levels less than approximately 100 mg/dl are associated with spontaneous and procedure-related bleeding 1
• A fibrinogen threshold from 100 to 200 mg/dl has been recommended to trigger fibrinogen replacement in bleeding patients with cirrhosis 1

Implementation Considerations

• If using a fibrinogen-based strategy, rapid laboratory testing should guide when empiric fibrinogen should not be used 1
• Fibrinogen administration using viscoelastic methods as guidance may be preferable to laboratory measurements of fibrinogen levels 2
• When using coagulation factor concentrate-based strategies, treatment should be based on standard laboratory coagulation parameters and/or viscoelastic evidence of functional coagulation factor deficiency 1

Potential Pitfalls and Caveats

• Some methodological issues exist in laboratory methods to measure fibrinogen concentration 1
• In the presence of artificial colloids such as hydroxyethyl starch, even the recommended Clauss method may significantly overestimate the actual fibrinogen concentration 1
• The risk of thrombotic complications from excessive fibrinogen supplementation should be considered, though current evidence suggests fibrinogen concentrate has a good safety profile 6, 3
• Randomized controlled trials on fibrinogen supplementation have shown mixed results, with most studies being small and underpowered 1