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What evidence supports the use of fibrinogen concentrate to minimize the need for blood transfusions?

Introduction

Historically during pandemics, challenges are faced by blood banks in securing and protecting the blood supply.1 Though the demand for blood supply may decrease during a pandemic due to the postponement of elective surgeries, the procurement of blood supply through blood donations has seen a significant decrease during the coronavirus disease 2019 (COVID-19) pandemic compared to pre-pandemic years. The main reasons cited for the reduction in blood donations include the precautions issued by local governments to socially distance, which reduces the number of available donors, as well as the safety of the blood supply due to the potential for viral transmission of COVID-19.1,2 To reduce the need for blood during the ongoing blood shortage, a variety of modalities that are safe and effective have been explored in the literature. One of these options involves the administration of fibrinogen concentrate (FC), which is a purified, virus inactivated, lyphophilized fibrinogen extracted from human plasma.3 Fibrinogen, the substrate of thrombin, is involved in primary and secondary hemostasic mechanisms, and is responsible for inducing platelet activation and aggregration. Both RiastapÒ and FibrygaÒ, human FCs approved by the U.S. Food and Drug Administration (FDA), act to replace fibrinogen, which is consumed during hemostasis, and are only approved for the treatment of adult and pediatric patients with congenital fibrinogen deficiency, an autosomal recessive rare bleeding disorder, to replace missing or low levels of coagulation factor.3,4,5  The use of FC to reduce the need for blood transfusion during critical blood shortages is not FDA-approved; use of the agent for this indication is considered off-label.4,5

Currently, recommendations already exist regarding the use of FCs for the perioperative management of bleeding due to hypofibrinogenemia. The American Society of Anesthesiologists (ASA) Task Force on Perioperative Blood Management practice guidelines recommend considering the use of FCs for excessive bleeding with hypofibrinogenemia, with insufficient evidence to recommend the use intraoperatively versus post-operatively.6 The Task Force also states that the literature is insufficient to evaluate the use of cryoprecipitate, the alternative, for the management of hypofibrinogenemia intraoperatively or post-operatively.  Beyond guideline recommendations from the ASA, 2 groups have cited recommendations for the use of FCs to mitigate the need for blood products like cryoprecipitate during the ongoing national blood supply shortage.7,8 Cryoprecipitate infusion, another method of repleting fibrinogen, is a blood product obtained from thawed plasma that is a precipitated fraction of von Willebrand factor, Factor VIII, and fibrinogen.3,9 Cryoprecipitate is typically given in patients with active bleeding or in those at high risk due to low levels of fibrinogen (< 100 mg/dL) or hyperfibrinolytic activity, and is considered a more efficient source of fibrinogen administration when compared to plasma treatment.3,9 The College of American Pathologists (CAP) Transfusion, Apheresis and Cellular Therapy (TACT) Committee recommends considering FCs as a method of pharmacologic hemostasis to replace cryoprecipitate if blood supplies are depleted.7 Additionally, as a recommended strategy for managing blood product shortages, the American Red Cross recommends that during severe shortages, defined as a hospital inventory 75% lower than anticipated, the use of FC be implemented to reduce the need for cryoprecipitate.8 The American Red Cross 2021 guidelines also acknowledge that the substitution of alternative fibrogen products is an area of ongoing research, with further data still needed on the appropriate timing of FC administration, as well as the impact on clinical outcomes.10

Literature Review
A Cochrane review conducted in 2013 of the available literature on bleeding patients suggested a beneficial effect of FC in reducing allogeneic blood transfusions based on low quality evidence.11 A 2018 Cochrane review evaluating haemostatic factors found no evidence that FC reduced all-cause mortality in actively bleeding patients when assessed versus an inactive comparator or another treatment.12 Additionally, there was no evidence that FC increased the risk of arterial or venous thromboembolism versus an inactive comparator when given in actively bleeding patients, or when compared against another treatment. When used prophylactically, the review also found no evidence that FC reduced all-cause mortality versus placebo, with low to moderate quality evidence that FC did not increase the risk of venous or arterial thromboembolism.

Since the initial 2013 review, numerous randomized controlled trials (RCTs) and meta-analyses (MAs) have been published evaluating the impact of fibrinogen concentrate administration on transfusion requirements. An updated search of the Pubmed database was conducted in May 2022 to identify recent RCTs and MAs evaluating the clinical outcomes of fibrinogen concentrate in surgical patients to reduce the need for allogeneic blood transfusions. 13-19 Many recently published RCTs have already been pooled in MAs and are therefore not summarized individually in this update. Table 1 provides a summary of the literature included in this review.

Overall, newer evidence has demonstrated a reduction in the volume of blood loss post-operatively, with unclear effects on all-cause mortality.13,14,15 In 1 MA of 13 RCTs, administration of FC was found to significantly reduce blood loss up to 12 hours post-operatively, but did not result in less allogeneic blood product (ABP) use.13 In 2 MAs of 8 and 14 RCTs, the effects of FC on all-cause mortality were conflicting, with FC administration resulting in similar rates with active comparator in one study, and in the other MA, a benefit observed with FC use.14,15 Both MAs, however. observed similar rates of thromboembolism with FC versus comparator, and a decreased need for either ABP or packed red blood cells (pRBCs).

Since the publication of the aforementioned MAs, 4 additional RCTs evaluating perioperative FC have been published.16,17,18,19 One trial compared 4 grams of FC to 10 units of cryoprecipitate given after cardiac bypass if clinically relevant bleeding was observed. The administration of 4 grams of FC resulted in similar ABP requirements between groups within the first 24-hours post-operatively, with FC determined noninferior to the administration of cryoprecipitate (p<0.001 for noninferiority).18 Based on each component of ABP (e.g., platelets, plasma, red blood cells) transfused post-operatively, FC demonstrated noninferiority versus cryoprecipitate, with no increases in thromboembolism observed between groups up to 28 days post-operatively. Two clinical trials evaluating FC versus placebo with continuous tranexamic acid or fresh frozen plasma (FFP) infusion resulted in different outcomes regarding blood product usage.17,19 The first trial evaluated FC or placebo in 62 patients on a background of continuous tranexamic acid and found similar usage of blood products over a 24-hour period.17 The other trial, conducted in 20 patients, demonstrated a reduction in the units of ABP required over a 24- hour period in favor of FC over FFP when each were given as a continuous infusion.19 Another trial in 70 patients compared 2 grams of preoperative FC to placebo, and found significant reductions in blood loss with FC administration and a reduced need for pRBCs versus placebo.16

Additionally, while the ASA Task Force recommends the usage of FC in hypofibrinogenemia, the plasma fibrinogen level necessary to warrant treatment is unclear.6 The European Society of Anesthesiology (ESA) guidelines, however, define hypofibrinogenemia as a plasma concentration of less than 1.5 to 2 g/dL.20 Across the trials listed in Table 1, the fibrinogen level required for dosing differed. One trial required preoperative plasma fibrinogen levels <3.8 g/dL for prophylactic FC administration, while another dosed FC if levels were below 3.8 g/dL with diffuse clinical bleeding.16,17 A third required fibrinogen levels of < 2 g/dL before FC administration during surgery (in accordance with ESA guidance), while another trial adjusted FC infusions based on a target FIBTEM A10 of < 8 mm.18,19 The FIBTEM A10 assay, or measure of clot firmness at 10 minutes determined by thromboelastometry, can be used to estimate fibrinogen levels and guide the replacement of fibrinogen during excessive blood loss.21 Across the meta-analyses, included trials had preoperative fibrinogen levels of less than 3.8 g/dL or 2.9 g/dL, did not report preoperative levels, or relied on other criteria for the administration of FC.13,14,15

Table 1. Clinical outcomes with fibrinogen concentrate for reduction of blood transfusion13-19
Citation/DesignPopulation
InterventionsPrimary OutcomeOther outcomes
Meta-analyses
Ng 202013

MA of 13 RCTs		900 surgical patients
FC (1 to 6 grams, or 30 mg/kg to 45 mg/kg)

Comparator (placebo, saline, no treatment)

Given intra-, pre-, or post-operatively		Blood loss up to 12 hours post-op: Less with FC vs comparator (MD -134.6 mL; p<0.00001)Intraoperative blood loss: Similar with FC vs comparator (MD -66.5 mL; p=0.10)

Amount of RBCs first 24 hours post-op: Similar with FC vs comparator (MD -0.3 units; p=0.25)

Amount of FFP first 24 hours post-op: Similar with FC vs comparator (MD 0.2 units; p=0.72)

Amount of platelets first 24 hours post-op: Similar with FC vs comparator (MD 0.1 units; p=0.30)

Incidence of thromboembolism: Similar with FC vs comparator (OR 0.2; p=0.08)
Li 201814

MA of 8 RCTs
597 patients undergoing cardiac surgeryFC (dose of 1 to 8 grams)

Comparator (Placebo, SOC, albumin, 1 unit of platelets)

Given pre- or intraoperatively		All-cause mortality: Similar rates between FC and comparator (RR 0.41; 95% CI 0.12 to 1.38)Incidence of ABP transfusion: decreased with FC vs comparator (RR 0.64; 95% CI 0.49 to 0.83).

Incidence of plasma transfusion: similar with FC vs comparator (RR 0.6; 95% CI 0.28 to 1.29)

Incidence of platelet transfusion: similar with FC vs comparator (RR 0.62; 95% CI 0.29 to 1.33)

Incidence of DVT or PE: similar with FC vs comparator (RR 2.85; 95% CI 0.12 to 68.83)
Fominskiy 201615

MA of 14 RCTs		1,035 surgical patients; the majority undergoing cardiac surgeryFC (dose 500 mg to 4 grams, or from 30 to 60 mg/kg, based on fibrinogen plasma concentration, or target FIBTEM)

Comparator (Placebo, cryoprecipitate, FFP, platelets, or no treatment)

Given pre-, intra-, or post-operatively		All-cause mortality: lower rates in FC group (0.9% vs 3.5%, respectively; p=0.02).Reduced bleeding with FC vs comparator (MD -127 mL; p=0.002)

Lower units of pRBC transfused vs comparator (MD -0.9; p<0.001).

Similar rates of thrombosis between FC and comparator (0.7% vs 2.3%; p=0.14)
Randomized Controlled  Trials
Fathi 202116

DB, PC, RCT		70 men undergoing radical cystectomyFC 2 grams

Placebo

Given preoperatively		Blood loss up to 48 hours post op: FC reduced the volume of blood loss vs placebo (mean 591 mL vs 1077 mL, respectively; p<0.001)Reduced amount of packed cells with FC vs placebo (median 1 and 2 units, respectively; p=0.002)
Kwapisz 202017

DB, Prospective RCT
62 patients undergoing high-risk, cardiac surgeryFC* administered prophylactically. Dose calculated based on FIBTEM assay

Placebo*

*Patients also received continuous infusion of TXA		Blood product usage first 24 hours: Similar usage between  FC and placebo groups (19 vs 37 units, respectively; p=0.908)FIBTEM MCF: Greater median clotting in FC vs placebo group (27 mm vs 23 mm, respectively; p=0.022).

Greater median PTT in FC vs placebo group (31s vs 28.5s, respectively; p=0.035)

Similar blood drainage between groups at 24 hours (371 mL vs 470 mL, respectively; p=0.127)
Callum 201918

MC, NI, RCT

20% NI margin		827 patients undergoing cardiac surgeryFC 4 grams

Cryoprecipitate 10 units

Given within 24 hours post-bypass if clinically significant bleeding		Units ABP first 24 hours post-op: FC noninferior to cryoprecipitate (mean 16.3 vs 17 units;  p<0.001 for noninferiority; p=0.50 for superiority)Units of RBCs first 24 hours post-op: FC noninferior to cryoprecipitate (MD 0.23 units; p=0.02 for noninferiority)

Platelet transfusions first 24 hours post-op: FC noninferior to cryoprecipitate (MD -0.46 units; p<0.001 for noninferiority)

Plasma transfusions first 24 hours post- op: FC noninferior to cryoprecipitate (MD -0.04 units; p=0.008 for noninferiority)

Thromboembolism at 28 days: Similar with FC vs cryoprecipitate (OR 0.70; 95% CI, 0.42 to 1.2)
Morrison 201919

Pilot RCT		20 patients undergoing thoraco-AAA surgeryFC infusion approximately 40mg/kg/hour*

FFP infusion approximately 15 mL/kg/hour*(40mg/kg/hour of fibrinogen)

*Infusions adjusted during surgery based on FIBTEM assay		Units ABP first 24 hours post-op: Fewer units required with FC vs FFP (median 4.5 vs 22.5 units, respectively; p=.011)Postoperative fibrinogen concentrations: Similar with FC vs FFP (1.6 g/L vs 1.6 g/L, respectively; p=0.36)

Mean postoperative INR lower with FFP vs FC (1.1 vs 1.8, respectively; p<0.0001)
Abbreviations: AAA=abdominal aortic aneurysm; ABP=allogeneic blood products; CI=confidence interval; DB=double-blind; DVT=deep vein thrombosis; FC=fibrinogen concentrate; FIBTEM=fibrin specific ROTEM test; FFP=fresh frozen plasma; INR=International Normalized Ratio; MA=meta anlaysis; MCF=maximum clot firmness; MC=Multicenter; MD=mean difference; NI=noninferiority; OR=odds ratio; pRBC=packed red blood cells; PC=placebo-controlled; PE=pulmonary embolism; PTT=partial thromboplastin time; RBC=red blood cells; RCT=randomized controlled trial; ROTEM=rotational thromboelastometry; RR=risk ratio; SOC=standard of care; TXA=tranexamic acid

Summary

Despite the amount of new published literature on the use of FC in bleeding patients, the evidence is still lacking regarding the optimal dose, dose timing, efficacy, and safety in reducing the need for blood transfusions. Differences in dosing approaches, as well as the timing of FC administration make the generalizability of study findings difficult. In general, newer evidence suggests a reduction in perioperative blood loss with FC use versus placebo, with no robust evidence of FC versus active comparator agents. The effects of FC use on all-cause mortality were similar or lower across studies, and the use of FC does not appear to increase the risk for thromboembolism. Administration of FC has been shown to reduce the need for some ABP transfusions, however, the number of studies using placebo or saline as a comparator limits this finding. Further studies may help elucidate the optimal perioperative dosing regimen for the use of FCs to reduce blood product usage during blood shortages.

References

  1. Al Mahmasani L, Hodroj MH, Finianos A, Taher A. COVID-19 pandemic and transfusion medicine: the worldwide challenge and its implications. Ann Hematol. 2021;100(5):1115-1122. doi:10.1007/s00277-021-04441-y
  2. Chang L, Yan Y, Wang L. Coronavirus Disease 2019: Coronaviruses and blood safety. Transfus Med Rev. 2020;34(2):75-80. doi:10.1016/j.tmrv.2020.02.003
  3. Schoettker P, Marcucci CE, Casso G, Heim C. Revisiting transfusion safety and alternatives to transfusion. Presse Med. 2016;45(7-8 Pt 2):e331-e340. doi:10.1016/j.lpm.2016.06.023
  4. Riastap [package insert]. Marburg, Germany: GSL Behring GmBH; 2021.
  5. Fibryga [package insert]. Vienna, Austria: Octapharma; 2020.
  6. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management. Anesthesiology. 2015;122(2):241-275. doi:10.1097/ALN.0000000000000463
  7. College of American Pathologists (CAP) Transfusion, Apheresis and Cellular Therapy Committee. The coronavirus emergency and the US blood supply. Updated 2020 March 27. From CAP website. https://www.cap.org/laboratory-improvement/news-and-updates/the-coronavirus-emergency-and-the-us-blood-supply-college-of-american-pathologists-transfusion-apheresis-and-cellular-therapy-committee
  8. American Red Cross. Recommended strategies for managing blood product shortages. 2021 Dec. https://www.redcrossblood.org/content/dam/redcrossblood/hospital-page-documents/RecommendedStrategiesManagingBloodProductShortages.pdf
  9. Arruda VR, High KA. Coagulation Disorders. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e. McGraw Hill; 2018. Accessed May 20, 2022. https://accessmedicine-mhmedical-com.proxy.cc.uic.edu/content.aspx?bookid=2129§ionid=192018684
  10. American Red Cross. Compendium of transfusion practice guidelines, Edition 4. 2021 Jan. https://www.redcrossblood.org/content/dam/redcrossblood/hospital-page-documents/334401_compendium_v04jan2021_bookmarkedworking_rwv01.pdf
  11. Wikkelsø A, Lunde J, Johansen M, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev. 2013;2013(8):CD008864. Published 2013 Aug 29. doi:10.1002/14651858.CD008864.pub2
  12. Fabes J, Brunskill SJ, Curry N, Doree C, Stanworth SJ. Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia. Cochrane Database Syst Rev. 2018;12(12):CD010649. Published 2018 Dec 24. doi:10.1002/14651858.CD010649.pub2
  13. Ng KT, Yap JLL, Kwok PE. The effect of fibrinogen concentrate on postoperative blood loss: A systematic review and meta-analysis of randomized controlled trials. J Clin Anesth. 2020;63:109782. doi:10.1016/j.jclinane.2020.109782
  14. Li J, Gong J, Zhu F, et al.  Fibrinogen concentrate in cardiovascular surgery: A meta-analysis of randomized controlled trials.  Anesthesia & Analgesia.  2018; 127 (3): 612-621.  doi: 10.1213/ANE.0000000000003508.
  15. Fominskiy E, Nepomniashchikh VA, Lomivorotov VV, et al. Efficacy and Safety of Fibrinogen Concentrate in Surgical Patients: A Meta-Analysis of Randomized Controlled Trials. J Cardiothorac Vasc Anesth. 2016;30(5):1196-1204. doi:10.1053/j.jvca.2016.04.015
  16. Fathi M, Lashay A, Massoudi N, Nooraei N, Nik MA. Fibrinogen prophylaxis for reducing perioperative bleeding in patients undergoing radical cystectomy: A double-blind placebo-controlled randomized trial.J Clin Anesth. 2021;73:110373. doi:10.1016/j.jclinane.2021.110373
  17. Kwapisz MM, Kent B, DiQuinzio C, et al. The prophylactic use of fibrinogen concentrate in high-risk cardiac surgery. Acta Anaesthesiol Scand. 2020;64(5):602-612. doi:10.1111/aas.13540
  18. Callum J, Farkouh ME, Scales DC, et al. Effect of fibrinogen concentrate vs cryoprecipitate on blood component transfusion after cardiac surgery: The FIBRES randomized clinical trial. JAMA. 2019;322(20):1966-1976. doi:10.1001/jama.2019.17312
  19. Morrison GA, Koch J, Royds M, et al. Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial. Anaesthesia. 2019;74(2):180-189. doi:10.1111/anae.14495
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  21. de Vries JJ, Veen CSB, Snoek CJM, Kruip MJHA, de Maat MPM. FIBTEM clot firmness parameters correlate well with the fibrinogen concentration measured by the Clauss assay in patients and healthy subjects.Scand J Clin Lab Invest. 2020;80(7):600-605. doi:10.1080/00365513.2020.1818283

Prepared by:
Christie Denton, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2022

The information presented is current as of May 23, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.