Efficacy and safety of fibrinogen concentrate for on‐demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency

Khayat, Claudia Djambas; Lohade, Sunil; D'Souza, Fulton; Shamanur, Latha G; Zekavat, Omid Reza; Kruzhkova, Irina; Schwartz, Bruce A.; Solomon, Cristina; Knaub, Sigurd; Peyvandi, Flora

doi:10.1111/hae.14230

Cited by 14 publications

(51 citation statements)

References 26 publications

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“…23 Further studies dissecting the differential contributions on prothrombin conversion and thrombin decay showed that fibrinogen slowed down the inactivation of thrombin and that fibrinogen itself stimulated prothrombin conversion. 24 The fact that in vivo TG is increased is supported by the observation of elevated plasma levels of TAT complexes, which decrease after FC infusion 25 26 27 ; in our study however, we failed to show such a variation. The unexpected finding that at the same time TG is somewhat delayed (i.e., prolonged lag time after fibrinogen infusion) deserves further studies.…”

Section: Discussionmentioning

confidence: 48%

Impact of Fibrinogen Infusion on Thrombin Generation and Fibrin Clot Structure in Patients with Inherited Afibrinogenemia

et al. 2022

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Introduction: Inherited afibrinogenemia is a very rare disease characterized by complete absence of fibrinogen in the circulation and an increased risk in both thrombosis and bleeding. Infusion of fibrinogen concentrate (FC) is the main approach for prevention and management of bleeding; however, it has been reported to carry a thrombotic risk. Methods: We investigated the impact of a standard dose (40-100 mg/kg) of FC infusion on the thrombin generation (TG) parameters and the fibrin clot structure formed in plasma samples of patients with afibrinogenemia. Blood samples were collected from 20 patients before (T0) and 1 hour after infusion of FC (T1). TG was studied with Calibrated Automated Thrombography. Fibrin clot structure was assessed with turbidimetry and scanning electron microscopy (SEM). Results: FC infusions (mean Clauss fibrinogen plasma level 1.21 g/L at T1) led to a statistically significant increase in endogenous thrombin potentials (ETP) (p<0.0001) and thrombin peaks (p=0.02). Nevertheless, when compared to healthy controls, patients’ T1 lag times were longer (p=0.002), ETP values were lower (p=0.0003), and thrombin peaks were lower (p<00001). All fibrin polymerization parameters (turbidimetry) obtained at T1 were comparable to those of patients with inherited hypofibrinogenemia matched for fibrinogen plasma levels. Conclusions: In summary, fibrinogen infusion with a standard dose of FC increased but did not correct TG and led to formation of fibrin clots similar to those of patients with hypofibrinogenemia. All in all, our results do not support to biological evidence of hypercoagulability induced by FC in patients with afibrinogenemia.

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Section: Discussionmentioning

confidence: 48%

Impact of Fibrinogen Infusion on Thrombin Generation and Fibrin Clot Structure in Patients with Inherited Afibrinogenemia

et al. 2022

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“…Fibrinogen concentrate is used clinically to improve hemostasis in bleeding patients, based on studies that have demonstrated that there are associations between low plasma concentration of fibrinogen and increased bleeding volumes and transfusion requirements 3–5 . Supplementation with fibrinogen concentrates improves clot strength and is therefore used in patients with inherited and acquired hypofibrinogenemia 9–12,18,19 …”

Section: Discussionmentioning

confidence: 99%

A comparison of the in vitro effects of three fibrinogen concentrates on clot strength in blood samples from cardiac surgery patients

Stolt

Hakimi

Singh

et al. 2021

Acta Anaesthesiol Scand

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Background Fibrinogen concentrate is used clinically to improve hemostasis in bleeding patients. We investigated and compared the efficacy of three commercially available fibrinogen concentrates to improve clot strength in blood samples from cardiac surgery patients. Objectives Postoperative blood samples were collected from 23 cardiac surgery patients. Samples were each divided into four vials, each supplemented with 1.125 mg of fibrinogen of one of three fibrinogen concentrates (RiaSTAP®, Fibryga®, FibCLOT®), or placebo. The fibrinogen dose corresponded to 2.5 g per 70 kg of body weight. Clot strength after supplementation was assessed in duplicate with rotational thromboelastometry (ROTEM®) using FIBTEM maximum clot firmness, EXTEM clot formation time, and maximum clot firmness assays. Results In vitro fibrinogen concentrate supplementation of the samples resulted in higher plasma fibrinogen concentrations and improved clot strength with all three concentrates. Supplementation with FibCLOT increased FIBTEM maximum clot firmness (+46% [25th–75th percentile 35–55] compared to placebo) significantly more than did supplementation with Fibryga (+26% [21–35]) and RiaSTAP (+29% [22–47], p < .001). FibCLOT supplementation also shortened EXTEM clot formation time and increased EXTEM maximum clot firmness to a greater extent than did the other concentrates (both p < .001). Conclusions At the selected dose, FibCLOT was more effective than Fibryga and RiaSTAP in restoring clot strength in postoperative blood samples from cardiac surgery patients. These results may have implications for the choice of fibrinogen concentrate and dosing.

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“…FORMA‐02 (NCT02267226), performed in adults/adolescents (aged ≥12 years), 14 and FORMA‐04 (NCT02408484), performed in children (aged <12 years), 12 were multinational, multicenter, prospective, open‐label, uncontrolled Phase 3 studies to assess HFC efficacy and safety for the on‐demand treatment of bleeding episodes (BEs) and surgical prophylaxis in patients with CFD. Designs of these trials have been described previously 12,14 . Data presented herein are for all surgical patients included across these two studies.…”

Section: Methodsmentioning

confidence: 99%

“…All clinical efficacy assessments were adjudicated by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC). Overall hemostatic efficacy was assessed using a 2‐point scale: treatment success or failure 12,14 …”

Section: Methodsmentioning

confidence: 99%

“…We previously reported results from two Phase 3 studies on HFC efficacy and safety ( Fibryga , Octapharma AG) in adults/adolescents (FORMA‐02; n = 25), 14 and in pediatric patients (FORMA‐04; n = 14) with CFD 12 . In both studies, this HFC was efficacious for on‐demand bleeding episode (BE) treatment and surgical prophylaxis, and exhibited a favorable safety profile.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of fibrinogen concentrate for perioperative prophylaxis of bleeding in adult, adolescent, and pediatric patients with congenital fibrinogen deficiency: FORMA‐02 and FORMA‐04 clinical trials

et al. 2022

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Background: Congenital fibrinogen deficiency (CFD) is a rare coagulation disorder placing patients at increased bleeding risk. Human fibrinogen concentrate (HFC) represents current standard of care for fibrinogen replacement in CFD, however, limited data are available on HFC for prophylactic administration before/during surgery. Here, we report results and dosing considerations for HFC treatment in perioperative bleeding management in adult, adolescent, and pediatric patients with CFD.Study Design and Methods: FORMA-02/FORMA-04 were multinational, prospective, open-label, uncontrolled Phase 3 HFC efficacy/safety studies for surgical bleeding prophylaxis in adult/adolescent (≥12 years) and pediatric patients (<12 years) respectively. HFC dosing was calculated to achieve preestablished target fibrinogen plasma levels. Overall hemostatic efficacy was assessed as success/failure by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) according to objective criteria.Results: Twelve patients (≥12 years, N = 9; <12 years, N = 3) received HFC for surgical prophylaxis (15 surgeries; 13 minor, 2 major). Eleven minor surgeries in patients aged ≥12 years required a median of 1 infusion (range; 1-5), with a mean (±SD) dose of 93.50 mg/kg [±41.43] and two minor surgeries in patients <12 years required 1 infusion (91.55 mg/kg [±23.40]). The major surgery in an adult patient required eight infusions (225.3 mg/kg total dose). The major surgery in a pediatric patient required six infusions (450.4 mg/kg). All surgeries were rated successful by the IDMEAC. Discussion: In adults/adolescents and pediatric patients with fibrinogen deficiency, HFC treatment for hemostatic management during/after minor and major surgery was successful, with efficacy comparable across the different age groups.

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Efficacy and safety of fibrinogen concentrate for on‐demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 14 publications

References 26 publications

Impact of Fibrinogen Infusion on Thrombin Generation and Fibrin Clot Structure in Patients with Inherited Afibrinogenemia

Impact of Fibrinogen Infusion on Thrombin Generation and Fibrin Clot Structure in Patients with Inherited Afibrinogenemia

A comparison of the in vitro effects of three fibrinogen concentrates on clot strength in blood samples from cardiac surgery patients

Efficacy and safety of fibrinogen concentrate for perioperative prophylaxis of bleeding in adult, adolescent, and pediatric patients with congenital fibrinogen deficiency: FORMA‐02 and FORMA‐04 clinical trials

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