Clinical Guidelines

Title:
FIBRINOGEN CONCENTRATES FOR ACQUIRED FIBRINOGEN DEFICIENCY
Process Owner(s): Document No :
CG-ANA-GEN-06
Dr Jensen Ng
Effective Date :
Consultant
01 Mar 2019
Review Date :
01 Mar 2019
Approval: Revision No :
HOD, Anaesthesiology, Intensive Care and Pain Medicine 0.0

Key Search Terms: Fibrinogen, concentrates, deficiency

1.0 Introduction

1.1 Fibrinogen is the precursor of fibrin, which polymerises into a fibrin mesh, forming
the basis for haemostasis. In massive bleeding, fibrinogen is the first clotting factor
to deplete to critical levels [1]. Reduced fibrinogen levels are associated with
increased bleeding [2, 3] and mortality [4].

Limitations of cryoprecipitate
Locally, the standard fibrinogen replacement therapy is cryoprecipitate. However
this has several limitations:
1a. Need for cross-matching
1b. Requires thawing (up to 10 minutes) and collection from blood bank
1c. Variable fibrinogen content (ranging from 8 to 16 g/L)
1d Risk of pathogen transmission
1e. Risk of thromboembolism when given in large volumes
In the context of massive bleeding, (1a) and (1b) may delay timely fibrinogen
replacement.

1.2 Fibrinogen concentrate (FC) contain lyophillised human fibrinogen which are
stable in storage for up to 5 yrs. FIBRYGA® (Octapharma) is available as 1g vials for
reconstitution with 50mls sterile water for injection, and remains stable for up to
24 hours at 25°C.

Advantages of FC:
2a. Stored at room temperature at site of use (OT Complex)
2b. Does not require cross-matching
2c. Rapid reconstitution
2d. Consistent fibrinogen content
2e. Lower risk of pathogen transmission

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 2f. No increased risk of thromboembolic complications compared to
cryoprecipitate [9, 10, 11]

(2a), (2b) and (2c) may facilitate more rapid fibrinogen replacement. Several
retrospective studies have found that early replacement of fibrinogen (using either
cryoprecipitate or fibrinogen concentrate) is associated with reduced blood product
transfusion and improved mortality [5, 6], particularly if guided by point-of-care
viscoelastic haemostatic assays (VHA) e.g. ROTEM [7, 8].
This document describes the indications and administration of Fibrinogen
Concentrate in life-threatening bleeding with fibrinogen deficiency.

2.0 Indications and Contraindications for use

2.1 Indications:
FC use is indicated if there are both:
- Life-threatening bleed
- Proven fibrinogen deficiency (see section 3 below)
2.2 Contraindications:
FIBRYGA® (Octapharma) is contraindicated in individuals who have manifested
severe immediate hypersensitivity reactions, including anaphylaxis, to FIBRYGA or its
components (Sodium Citrate Dihydrate; Glycine; L-Arginine hydrochloride) [13].

3.0 Fibrinogen deficiency and dosing of FC
It is recommended to use a FIBTEM and EXTEM to guide the use of FC. The FC dose
will depend on the FIBTEM amplitude.
Alternatively, FC can be given if plasma fibrinogen levels are low (as demonstrated
on standard lab tests). The FC dose can be calculated based on measured and target
fibrinogen levels.
See Annex A for dosing recommendations.

4.0 Obtaining FC
4g of FC is stored in the OT Pharmacy. This is roughly equivalent to two 10-unit doses
of cryoprecipitate (2g FC ~ 10 units cryoprecipitate).
FC can be ordered by an Anaesthesiology Senior Resident (SR) grade and above.
Provided the indications in 2.0 are met, no approval from a Haematologist is
required.
1g of FC costs $707.06 with GST.

5.0 Reconstitution
Each 1g vial of FC should be reconstituted with 50mls of sterile water for injection.
To minimise bubble formation, avoid turbulent injection of sterile water, and swirl
the vial instead of shaking. Once completely dissolved, draw up the solution in a
50mls syringe through the filter provided.

6.0 Administration
The reconstituted fibrinogen solution should be administered intravenously at the
rate of 1gm over 5 minutes.

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7.0 Adverse reactions [13]:

7.1 Hypersensitivity Reactions
Hypersensitivity reactions may occur. If early signs of hypersensitivity reactions
(including hives, generalized urticaria, tightness of the chest, wheezing, hypotension,
and anaphylaxis) or symptoms of allergic reactions occur, immediately discontinue
administration
7.2 Thrombotic events
Thrombotic events have been reported in patients receiving human fibrinogen
concentrate. Treatment with human fibrinogen concentrate has been associated
with risk of thrombosis at target fibrinogen levels that were less than 150 mg/dL. The
risk of thrombosis may be greater when the target fibrinogen plasma level is 150
mg/dL. Weigh the benefits of FIBRYGA administration versus the risks of thrombosis.
Patients receiving FIBRYGA should be monitored for signs and symptoms of
thrombosis.
7.3 Transmissible Infectious Agents
FIBRYGA is made from human plasma. Products made from human plasma may
contain infectious agents (e.g., viruses and the CJD agent that can cause disease).
The risk that such products will transmit an infectious agent has been reduced by
screening plasma donors for prior exposure to certain viruses, by testing for the
presence of certain current virus infections, and by a process demonstrated to
inactivate and/or remove certain viruses during manufacturing.
7.4 Data Collection Sheet
A Data Collection sheet will accompany every 1g vial of FC. The user needs to
complete all data fields of this sheet. This is for monitoring of FC usage for
appropriate use and safety. See Annex B for the information sheet.


8.0 References:

1. RAHE-MEYER, N., & Sorensen, B. (2011). Fibrinogen concentrates for management of bleeding.
Journal of Thrombosis and Haemostasis, 9(1), 1–5. http://doi.org/10.1111/j.1538-
7836.2010.04099.x

2. Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H, Sibony O, Mahieu-Caputo D,
Hurtaud-Roux MF, Huisse MG, Denninger MH, de Prost D. The decrease of fibrinogen is an early
predictor of the severity of postpartum hemorrhage. J Thromb Hae- most 2007; 5: 266–73.

3. Karlsson M, Ternstrom L, Hyllner M, Baghaei F, Flinck A, Skrtic S, Jeppsson A. Prophylactic
fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised
pilot study. Thromb Haemost 2009; 102: 137–44.

4. Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, Hess JR, Dubick MA,
Simon CD, Beekley AC, Wolf SE, Wade CE, Holcomb JB. The ratio of fibrinogen to red cells transfused
affects survival in casualties receiving massive transfusions at an army combat support hospital. J
Trauma 2008; 64: S79–85.

5. Nienaber U, Innerhofer P, Westermann I, et al. The impact of fresh frozen plasma vs coagulation
factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive
transfusion. Injury 2011; 42: 697–701

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6. Weiss G, Lison S, Glaser M, et al. Observational study of fi- brinogen concentrate in massive
hemorrhage. Blood Coagul Fibrinolysis 2011; 22: 727–34

7. Scho ̈ chl H, Nienaber U, Hofer G, et al. Goal-directed coagula- tion management of major trauma
patients using thromboe- lastometry (ROTEMVR )-guided administration of fibrinogen concentrate
and prothrombin complex concentrate. Crit Care 2010; 14: R55

8. Scho ̈chl H, Nienaber U, Maegele M, et al. Transfusion in trauma: thromboelastometry-guided
coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy.
Crit Care 2011; 15: R83

9. Ross, C., Rangarajan, S., & and, M. K. O. T. (2017). Pharmacokinetics, clot strength and safety of a
new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen
deficiency. Wiley Online Library. http://doi.org/10.1111/jth.13923

10. Lissitchkov, T., Madan, B., Khayat, C. D., Zozulya, N., Ross, C., Karimi, M., et al. (2018). Efficacy
and safety of a new human fibrinogen concentrate in patients with congenital fibrinogen deficiency:
an interim analysis of a Phase III trial. Transfusion, 58(2), 413–422. ttp://doi.org/10.1111/trf.14421

11. Curry, N., Foley, C., Wong, H., Mora, A., Curnow, E., Zarankaite, A., et al. (2018). Early fibrinogen
concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre,
randomised, double blind, placebo-controlled pilot trial, 1–9. http://doi.org/10.1186/s13054-018-
2086-x

12. Rossaint, R., Bouillon, B., Cerny, V., Coats, T. J., Duranteau, J., Fernández-Mondéjar, E., et al.
(2016). The European guideline on management of major bleeding and coagulopathy following
trauma: fourth edition. Critical Care, 1–55. http://doi.org/10.1186/s13054-016-1265-x

13. FIBRYGA® (Octapharma) Prescribing Information Leaflet



9.0 Document History
Initial Issue Date: 28 Feb 2019
Key changes in revision 0. Compared to previous revision 0:

Date Section Changes

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Annex A

Fibrinogen dosing recommendations

A. Based on ROTEM
Criteria: A5FIB <35mm and A5FIB <8mm

Dosing calculation: Fibrinogen dose (g) = [Targeted increase in A5FIB (mm) x body weight (kg)] / 160

Target: A5FIB of 12mm

(Courtesy of ROTEM / Dr Klaus Gorlinger)

B. Based on Plasma Fibrinogen Level [12, 13]
Criterion: Plasma Fibrinogen Level < 1.5 – 2.0 g/L

Dosing: Fibrinogen dose (g) = [Target Level (g/L) – Measured Level (g/L) / 18] x body weight (kg)

Target: Plasma Fibrinogen Level < 1.5 – 2.0g/L

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 BTS-REC-184-00

Annex B
Paste Patient’s ID sticker
Blood Transfusion Services

Date:____________________

Fibrinogen Concentrate (1g)
Storage: Do not store at > 30°C Expiry date :
Do not freeze
Product code : FIBR
Location : ____________

Ordering Physician: ____________________________MCR No: _______________

Date /Time Transfusion started : _____________by _________________________

Date / Time Transfusion ended : _____________ by _________________________



Criteria for use

Note: Fibrinogen concentrate should be used only in life-threatening bleed with evidence
of fibrinogen deficiency
**RETURN THIS FORM TO BLOOD TRANSFUSION SERVICE FOR RESUPPLY OF FIBRINOGEN CONCENTRATE**

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