Congenital Fibrinogen Deficiency Research Articles

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database

AbstractCongenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

Post-Marketing Observational Study of the Safety and Efficacy of Fibrinogen Concentrate in Congenital Fibrinogen Deficiency in Patients of All Ages

Background and Significance: Congenital fibrinogen deficiency (CFD) is a rare coagulation disorder characterized by a lack or low levels of functional fibrinogen leading to inadequate clot formation. Patients with CFD may experience severe or frequent bleeding episodes (BEs), either spontaneously or following trauma or surgery. Human fibrinogen concentrate (HFC; Fibryga® [Octapharma]) can restore hemostasis, and its efficacy and safety has been demonstrated in interventional clinical studies of adult and pediatric patients. The primary objective of this planned observational study is to collect real-world evidence to further assess the safety profile of this HFC, in patients of all ages with congenital fibrinogen deficiency, by characterizing the risks of thrombosis and anaphylaxis following its administration for treatment of bleeding (Figure 1). The observational data collected in this study will provide a more comprehensive safety profile of this HFC in patients of all ages following its marketing authorization. Study Design and Methods: FORMA-07 (NCT03793426) is a prospective, non-interventional, multicenter, observational, post-marketing study. Patients of all ages with a documented diagnosis of CFD (i.e., congenital afibrinogenemia or hypofibrinogenemia) requiring on demand HFC for BE treatment are eligible for inclusion (Table 1). Exclusion criteria include other coagulation disorders, history of anti-fibrinogen inhibitors, and participation in concurrent clinical studies. This study will examine a highly purified, plasma derived, double virus inactivated/eliminated, lyophilized HFC, which will be used according to individual country approval and labelling, and individually dosed as per the locally approved package insert. Independent ethical committee approval will be sought prior to study start and freely given, written informed consent obtained from all participants, or legal guardians in the case of pediatric patients. This study will be conducted in accordance with the ethical principles laid down in the Declaration of Helsinki. The primary endpoint is the incidence of thromboembolic adverse drug reactions (ADRs) . Serious ADRs, ADRs of special interest (including thromboembolic events and anaphylaxis), and thromboembolic monitoring using the Wells Score will be documented. Hemostatic efficacy will be assessed as a secondary endpoint by the study investigator using a robust 4-point objective scale from 2 to 24 hours following treatment. FORMA-07 is ongoing and actively enrolling patients of all ages with CFD. The study aims to enroll ~25 patients over 7 years, collecting data from 105 BEs (≥10 major BEs in 10 patients). Results of HFC safety and efficacy will be continually monitored throughout the study. Completion is expected Q4 2027.

Congenital fibrinogen deficiency: Experience from a tertiary center in South India

Congenital fibrinogen deficiency: Experience from a tertiary center in South India

Congenital Fibrinogen Deficiency Caused by Novel FGG Gene Mutation

To detect and analyze coagulation related indexes and genotypes of a patient with congenital fibrinogen deficiency and his family members, and to investigate the possible molecular pathogenesis. Four peripheral blood samples (proband and 3 family members) were collected and the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg), D-Dimer and eight coagulation factor indicators were detected. All exons and flanking sequences of the FGA, FGB, and FGG genes encoding the three peptide chains of fibrinogen were sequenced and analyzed by bioinformatics. Among the eight coagulation factors of the proband and the elder sister, F Ⅴ and F Ⅷ were slightly higher, TT was significantly prolonged, and Fg was significantly reduced. Sequencing results showed that c.901C>T heterozygous mutation existed in the FGG gene. Bioinformatics analysis showed that the mutation changed the original protein structure and reduced the number of hydrogen bonds. The fibrinogen gamma chain c.901C>T heterozygous mutation is the main cause of congenital fibrinogen deficiency in this family. This mutation is reported for the first time at home and abroad.

Congenital fibrinogen deficiency in Hemophilia Center Medical City/Baghdad

CONTEXT: Congenital fibrinogen deficiency is a rare inherited coagulation disorder with an estimated prevalence of 1:1,000,000 which is characterized by bleeding that varies from mild to severe and by an extremely low level or complete absence of plasma and platelet fibrinogen.AIMS: This study aims to assess prevalence, demographic parameters, clinical presentation, and hemostatic values in patients diagnosed with congenital fibrinogen deficiency.SETTINGS AND DESIGN: A retrospective descriptive study of patients diagnosed with congenital fibrinogen deficiency in Hemophilia Center/Medical City/Baghdad over a period of 7 years (from August 2008 to August 2015).SUBJECTS AND METHODS: The study included patients diagnosed with congenital fibrinogen deficiency. The confirmation of diagnosis was done based on a low fibrinogen assay. All the fibrinogen deficient patients were diagnosed on basis of having fibrinogen level (<150 mg/dl).RESULTS: There were 111 cases of other coagulation factors deficiency (rare bleeding disorders) registered in the center, congenital fibrinogen deficiency represented 25 (22.5%) of them. Out of 25 patients with congenital fibrinogen deficiency, 8 patients (32%) had fibrinogen level <20 mg/dl (afibrinogenemia) and 17 patients (68%) had fibrinogen level between (20 and 150 mg/dl) (hypofibrinogenemia). The males were 17 patients (68%) and females were 8 patients (32%). The consanguinity was present in 16 (64%) and 11 patients (44%) who had a positive family history of the diseases. The patients with afibrinogenemia mostly presented with hemarthrosis (22.7%) while patients with hypofibrinogenemia mostly presented with menorrhagia (50.0%). The patients who were their symptoms manifested before the 1st year of their age most frequently developed life-threatening bleeding (central nervous system and gastrointestinal bleeding) which were observed in 4 cases. Most of the patients included in this study were without complications (80%) while just one patient (4%) died due to gastrointestinal bleeding others were complicated with viral hepatitis, hepatitis B in one patient (4%) and 3 patients (12%) developed hepatitis C.CONCLUSIONS: Congenital fibrinogen deficiency founded to be one of the most frequent rare bleeding disorders among Iraqi patients, with a high rate of consanguineous marriage and positive family history. There was a high frequency of life-threatening bleeding among patients who develop symptoms before the 1st year of their age, without notable major complications among the majority of patients.

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

BackgroundCongenital fibrinogen deficiency (CFD) is a rare, inherited disorder affecting normal blood clotting function, where patients can experience severe and/or frequent bleeding episodes (BEs). Treatment with human fibrinogen concentrate (HFC) can prevent/arrest bleeding. There is a need for more data on the efficacy, pharmacokinetics (PK) and safety of HFC treatment in paediatric patients with CFD.MethodsHaemostatic efficacy of HFC (Fibryga®, Octapharma AG) for on‐demand treatment of bleeding and surgical prophylaxis in patients <12 years old was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) based on an objective 4‐point efficacy scale. Maximum clot firmness (MCF; surrogate marker of haemostatic efficacy), single‐dose PK and safety were also assessed.ResultsOf 14 patients receiving HFC (median [range] age 6.0 years [1.0–10.0]), eight received HFC for 10 BEs, three for surgical prophylaxis and 13 for PK. The IDMEAC rated haemostatic efficacy as 100% successful for on‐demand BE treatment (95% CI 69.15–100.00) and surgical prophylaxis (95% CI 29.24–100.00). After a mean first dose of 70.78 mg/kg for BEs, mean (±SD) MCF significantly increased from pre‐treatment to 1‐hour post‐infusion (3.3 mm [±1.77]; P = 0.0002), coinciding with haemostatic efficacy. PK parameters were favourable. Two possibly related adverse events occurred, including one serious (portal vein thrombosis). No allergic/hypersensitivity reactions or deaths were observed.ConclusionHFC treatment for on‐demand treatment of BEs and surgical prophylaxis was efficacious for this ultra‐rare paediatric population with congenital afibrinogenaemia and showed a favourable PK and safety profile.

Efficacy and Safety of Human Fibrinogen Concentrate for the Treatment of Patients with Congenital Fibrinogen Deficiency: Combined Results of the FORMA-02 and FORMA-04 Clinical Trials

Introduction: Congenital fibrinogen deficiency (CFD) is a rare disorder which results from a complete lack (afibrinogenemia) or low levels (hypofibrinogenemia) of functional fibrinogen. Treatment with human fibrinogen concentrate (HFC) can treat bleeding episodes and prevent blood loss in surgical treatment in patients with CFD. Herein we report combined data from two clinical studies on the efficacy and safety of HFC for the treatment of bleeding episodes (BEs) and surgical prophylaxis in adult, adolescent and pediatric patients. Methods: Both FORMA-02 and FORMA-04 were multinational, multicenter, prospective, open-label, uncontrolled Phase 3 studies for the use of HFC in adult and pediatric patients with CFD. They reported the hemostatic efficacy and safety of human fibrinogen concentrate (HFC: Fibryga® Octapharma) for on-demand treatment of BEs and surgical prophylaxis using objective criteria. Efficacy was assessed by the trial investigators and adjudicated by an independent data monitoring and end-point adjudication committee (IDMEAC). All adverse events (AEs) and serious AEs were recorded. Results: The two studies included a total of 39 patients who received HFC. The median (range) age across both studies was 17 (1-54) years, with 14 pediatric (aged 0-11), 6 adolescent (aged 12-18) and 19 adult patients (aged &amp;gt;18). Treatment of Bleeding Events 32 patients received HFC for the treatment of 99 bleeding events (BEs), 97 minor and 4 major. Of these, 72 were spontaneous, and 27 were due to trauma. 10 BEs occurred in pediatric patients (8 minor, 2 major), and 89 in adult/adolescents (87 minor, 2 major). The mean (±SD) total dose per BE was 65.51 mg/kg (±26.47) for adult/adolescent patients (ages 12-54) and 93.78 (±64.60) for pediatric patients (ages 0-11). Investigator-assessed and IDMEAC rated hemostatic efficacy are shown in Table 1. Overall hemostatic efficacy was rated as success (rating of excellent or good) for 99.0% of BEs by the IDMEAC. Treatment efficacy results were comparable when analyzed by age subgroup of adult (≥18 years), adolescent (&amp;gt;12-&amp;lt;18 years) and in two groups of pediatric patients (&amp;lt;6 years and 6-12 years). Surgical prophylaxis A total of 12 patients received HFC across 15 surgeries (13 minor and 2 major), 3 in pediatric patients (major: splenectomy; minor: circumcision and pulpectomy), and 12 in adults/adolescents (major: eye enucleation with socket reconstruction; minor: knee radioisotope synovectomy [n=2], dental extraction [n=3], circumcision [n=2], excision of circumcision scar bud, root canal operation, skin biopsy, and debridement of superficial necrosis). Mean (±SD) loading dose administered prior to surgery was 77.39 (±20.22) in adult/adolescent patients and 78.50 mg/kg (±27.96) for pediatric patients. Seven surgeries required multiple infusions, with the two major surgeries requiring 5 and 7 maintenance infusions, and the five minor surgeries requiring median (range) 3 (1-4) maintenance infusions. Intra- and post-operative hemostatic efficacy for all surgeries is shown in Table 1. Overall hemostatic efficacy of all the procedures was rated 100% successful by both the investigator and IDMEAC assessment. Safety A total of 101 AEs occurred in 23 patients (59.0%), including 16 serious AEs in 6 patients. Of these, 5 AEs in 4 patients were considered to be possibly related to treatment. These included a mild skin reaction (itchiness and redness), ischemia due to digital microthrombi, peripheral phlebitis of the upper limbs, and a portal vein thrombosis following splenectomy. No allergic/hypersensitivity reactions or deaths were observed during either of the studies. Conclusions: HFC treatment was shown to be efficacious for on-demand treatment of BEs and perioperative prophylaxis in this rare CFD population, across two Phase 3 clinical trials. Efficacy was comparable for adult, adolescent and pediatric patients. A favorable safety profile was seen for the treatment of patients with congenital afibrinogenemia with HFC. Disclosures Djambas Khayat: Octapharma: Research Funding. Kruzhkova:Octapharma: Current Employment. Solomon:Octapharma: Current Employment. Schwartz:Octapharma: Current Employment. Peyvandi:Octapharma: Research Funding. OffLabel Disclosure: On label use: Fibryga for treatment of bleeding episodes Off label use: Use of Fibryga as surgical prophylaxis in the US

Fibrinogen concentrate for bleeding in patients with congenital fibrinogen deficiency: Observational study of efficacy and safety for prophylaxis and treatment

BackgroundCongenital fibrinogen deficiency (CFD) is a rare bleeding disorder characterized by reduced levels (afibrinogenemia, hypofibrinogenemia) or dysfunctional fibrinogen (dysfibrinogenemia), for which fibrinogen supplementation is the mainstay treatment. ObjectivesTo assess the efficacy and safety of human fibrinogen concentrate (FCH) in patients with CFD. MethodsThis was a multicenter, noninterventional, retrospective cohort study with a 12‐month prospective follow‐up period in the United States and Canada. Individuals with CFD who received FCH for the treatment of bleeding, perioperative hemostasis, or prophylaxis were included. Data were collected retrospectively from medical records and every 3 months during the prospective period. Hemostatic efficacy was rated by the investigators as effective or ineffective using a 4‐point efficacy scale. Annualized bleeding rate (ABR) was summarized for patients who received FCH for routine prophylaxis. ResultsTwenty‐two patients were enrolled. FCH treatment was rated effective in treating ≥97.0% of bleeding events, in the retrospective and prospective periods. FCH was effective for perioperative hemostasis in ≥97.5% of minor and major surgeries across both periods. In patients treated with FCH for routine prophylaxis, the median ABRs for the retrospective and prospective period were 1.4 and 1.3, respectively. One adverse event (AE), thrombosis of the right cephalic vein, was reported as related to FCH treatment and resolved with a short course of anticoagulant. No serious AEs related to FCH or deaths were reported. ConclusionsIn patients with CFD, FCH is a well‐tolerated and effective treatment to achieve hemostasis during bleeding events and surgery and associated with infrequent bleeding events when used prophylactically.

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

BackgroundCongenital fibrinogen deficiency is an ultra‐rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. MethodsHemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA®, Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four‐point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. ResultsTwenty‐five afibrinogenemia patients were treated with HFC: 24 for on‐demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92‐0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95‐0.999). Mean ± standard deviation (SD) increase in MCF was 5.8 ± 2.5 mm one hour after the first HFC infusion (mean ± SD dose, 61.88 ± 11.73 mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80 mg/kg [34.09‐225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82‐1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. ConclusionsHuman fibrinogen concentrate was efficacious for on‐demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia.

Safety and Efficacy of Fibrinogen Concentrate in Congenital Fibrinogen Deficiency: A Post-Marketing Observational Study

Background: Congenital fibrinogen deficiencies (CFD), including afibrinogenemia and hypofibrinogenemia, are associated with severe and/or frequent bleeding episodes (BEs) that can occur spontaneously or following trauma. Human fibrinogen concentrate (HFC) has been shown to rapidly restore hemostasis in the event of such bleeding. The safety and efficacy of a new highly purified HFC have been demonstrated in interventional clinical studies; however, real-world evidence collected from routine clinical practice is needed to corroborate these data. Aims: The FORMA-07 study will collect real-world evidence from clinical practice concerning the safety and efficacy of a new HFC in the treatment of CFD. This highly purified, plasma-derived, lyophilized HFC undergoes two dedicated virus inactivation/removal steps during production. Methods: The FORMA-07 study is a post-marketing, multicenter observational study in adults and adolescents (≥12 years) with congenital afibrinogenemia or hypofibrinogenemia who are expected to require on-demand treatment with HFC for BEs. The study will examine treatment with a highly purified, plasma-derived, double virus inactivated/eliminated, lyophilized HFC (Octapharma). This Octapharma-sponsored study will seek approval from independent ethics committees prior to study start. Informed consent will be obtained from all subjects. Exclusion criteria include: other bleeding disorders, including acquired fibrinogen deficiency and dysfibrinogenemia; anti-fibrinogen inhibitors; participation in concurrent clinical studies. The study outline is shown in Figure 1. The primary endpoint is the incidence of thromboembolic adverse drug reactions (ADRs) in patients receiving HFC for on-demand treatment of BEs. Secondary endpoints include the hemostatic efficacy of HFC for treatment of all BEs recorded in the study (with focus on major BEs), assessed by the investigator using a 4-point objective scale within 2-24 hours following treatment. Safety endpoints include ADRs, serious ADRs, and ADRs of special interest (i.e., thromboembolic events and allergic reactions, including anaphylaxis). The planned study duration is up to 6 years and the study aims to enroll a minimum of 25 patients treated with HFC, to describe 105 BEs, including a minimum of 10 major BEs in 10 patients. During the observation period, enrolled patients may be treated for any BEs. Results: Results will be monitored on an ongoing basis and the study is expected to end Q2 2025. Conclusions: This study will collect real-world evidence for the safety and efficacy of HFC during routine clinical use in the treatment of bleeding in patients with congenital fibrinogen deficiency. Figure 1 Disclosures Schwartz: Octapharma: Employment. Peyvandi:Alnylam: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Octapharma: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Solomon:Octapharma: Employment. Knaub:Octapharma: Employment. Toth:Octapharma: Employment.

Clinical pharmacology, efficacy and safety study of a triple‐secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency

Essentials A novel fibrinogen concentrate was evaluated in patients with congenital fibrinogen deficiency. An open-label, phase 2-3 trial studied pharmacology, efficacy, and safety in patients >6years. The product offers safe and effective therapy in the treatment and prophylaxis of bleeding. Data in recovery show the need of adjusted treatment and further investigation in children. SUMMARY: Background Single-factor replacement therapy is considered the most suitable treatment option for hereditary fibrinogen deficiency. A triple-secured plasma-derived human fibrinogen product was developed to increase the safety of the former fibrinogen concentrate. Objectives This non-randomized, open-label, prospective study investigated pharmacokinetics, efficacy, and safety of a novel fibrinogen concentrate (FibCLOT® /CLOTTAFACT® LFB, France) in inherited deficiency. Patients/Methods Fourteen patients ≥40 kg received fibrinogen concentrate for pharmacology and 16 ≥ 23kg received treatment for bleeding or surgery. Each treatment was followed by a 3-week safety observation period. Key outcomes included number of infusions, dose, bleeding control, daily assessment, hemoglobin, blood loss, transfusions, and physicians' global assessment of response. Results Incremental recovery was 2.35mg mL-1 permgkg-1 and maximal concentration 1.41gL-1 (geometric mean) after 0.060gkg-1 infusion in 14afibrinogenemic patients. Terminal half-life was 69.3h (non-compartmental analysis). The maximum clot firmness was increased by a mean of 10.3mm from baseline to maximal effect. Sixteen patients participated to the efficacy phase: 32 bleeding episodes were treated in 9 patients, and 15 patients underwent 38 surgical/invasive procedures. All patients achieved appropriate hemostasis: response to treatment was successful in all bleeds (95% CI, 0.89-1.00) and procedures (95% CI, 0.91-1.00). Most (94%) bleeds were controlled with a single infusion (median 0.050g kg-1 ). Two patients experienced asymptomatic distal venous thromboses identified by systematic ultrasound. Conclusion FibCLOT® /CLOTTAFACT® showed a pharmacokinetic profile comparable to that of other fibrinogen concentrates and provides safe and clinically effective substitution therapy for fibrinogen-deficient patients.

Efficacy and Safety of Fibrinogen Concentrate for on-Demand Treatment of Acute Bleeding and for Surgical Prophylaxis in Subjects with Congenital Fibrinogen Deficiency — a Phase 3 Study

Introduction: Congenital afibrinogenemia is a rare inherited disorder characterized by an absence of plasma fibrinogen. Affected individuals have a highly variable bleeding tendency, which can be severe and include life-threatening bleeding and spontaneous/trauma-related bleeds. Therapeutic substitution with human fibrinogen concentrate (HFC) can correct the hemostatic defect and arrest bleeding. The FORMA-02 study investigated the hemostatic efficacy of a new plasma-derived, double virus-inactivated HFC (Fibryga, Octapharma) for on-demand treatment of bleeding episodes (BEs) and for surgical prophylaxis in patients with afibrinogenemia.Methods: FORMA-02 was a prospective, open-label, uncontrolled, multicenter Phase 3 study. A total of 25 patients with congenital afibrinogenemia (≥12 years) received the new HFC for treatment of a BE and/or for surgical prophylaxis. HFC was individually dosed to achieve a recommended target fibrinogen plasma level dependent on the bleeding type or surgery type (minor or major). The primary endpoint was the efficacy of the new HFC for on-demand treatment of the first BE after signed consent was obtained. Secondary endpoints included hemostatic efficacy of the HFC for the treatment of all BEs during the study period and its efficacy in preventing bleeding during and after surgery. Hemostatic efficacy was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) using objective four-point scales, with treatment success defined as a rating of excellent or good. Thromboelastometry maximum clot firmness (MCF) was also investigated as a surrogate marker of efficacy.Results: A total of 25 patients received the new HFC for treatment of a BE (N=24) and/or surgical prophylaxis (N=9). The mean±SD dose of HFC was 65.51±26.47 mg/kg per BE (89 events) and 40.45±30.78 mg/kg per surgery for surgical prophylaxis (12 events). Hemostatic efficacy for treatment of the first BE (primary endpoint) was rated as excellent or good for all patients by both the investigator and the IDMEAC (Success: 100%; 90% CI 0.89-1.00). When all BEs were evaluated (N=89 BEs in 24 patients), hemostatic efficacy was rated as excellent or good for 96.6% of events by the investigator and 98.9% by the IDMEAC. The first HFC infusion for treatment of the first BE for each patient led to a mean increase in blood fibrinogen concentration of 114.74±25.28 mg/dL 1 hour after administration, while the MCF increased by a mean of 6.48±3.07 mm.Intraoperative hemostatic efficacy for surgical prophylaxis was rated by the surgeon and the IDMEAC as excellent or good for 100% of the 12 surgeries that were performed (success: 100%; 90%CI 0.82-1.00). Postoperative efficacy was also rated as excellent or good in all cases. The first HFC infusion for each surgery led to a mean increase in blood fibrinogen concentration of 104.55±43.64 mg/dL at 1 hour after administration.A total of 15 serious adverse events (SAEs) occurred in 5 patients; only one was deemed to be related to the HFC by the investigator. This was a digital ischemia that resolved without sequelae. No inhibitory anti-fibrinogen antibodies were detected and there were no severe allergic or hypersensitivity reactions related to the HFC.Conclusions: These data indicate that the new HFC was efficacious for on-demand treatment of acute bleeding and for surgical prophylaxis in patients with congenital afibrinogenemia, with hemostatic efficacy rated as 100% in both settings. The HFC showed an acceptable safety profile in this study population. DisclosuresPeyvandi:Grifols: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau. Schwartz:Octapharma US: Employment. Knaub:Octapharma AG: Employment.

Efficacy and Pharmacokinetics of a New Fibrinogen Concentrate in Treating Acute Bleeding in Adolescent Patients with Congenital Fibrinogen Deficiency

Introduction: Individuals with congenital afibrinogenemia can experience frequent and/or severe bleeding episodes (BE). Human fibrinogen concentrate (HFC) can correct the hemostatic defect and arrest bleeding. We investigated the efficacy, safety and pharmacokinetics (PK) of a new highly purified, double virus-inactivated HFC (Fibryga, Octapharma) in adolescent patients.Methods: Data were analyzed from two multinational, prospective, open-label studies. FORMA-01 studied the PK of the new HFC vs. comparator (Haemocomplettan P), as well as surrogate efficacy and safety, after single infusion of 70 mg/kg. Surrogate efficacy was defined as thromboelastometric maximum clot firmness (MCF). FORMA-02 was a Phase 3 study in which the primary endpoint was the hemostatic efficacy of the new HFC for on-demand treatment of the first bleeding event. A 4-point objective scale, which was adjudicated by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC), was used for evaluation of efficacy. In addition, MCF and safety were evaluated for all BEs that occurred during the study period.Results: Data were available for 12 patients aged 12-17 years with afibrinogenemia. FORMA-01 included 5 patients aged 12-17 years (1 was excluded due to a protocol deviation); PK data for new HFC vs. comparator are shown in Table 1. For comparison, in adults from the same study AUCnorm was also larger and clearance slower for new HFC vs. comparator (both p=0.0027). At 1 h following infusion of new HFC or comparator, mean±SD MCF (n=6) increased from 0 mm to 9.0±2.0 and 8.8±2.6 mm, respectively (9.9±3.3 and 10.4±4.9 mm in adults).In FORMA-02, 6 adolescent patients received new HFC individually dosed for treatment of a BE. Hemostatic efficacy for treatment of the first BE was rated as excellent for all patients (success: 100%; 90% CI: 0.655-1.000). When taking all BEs into account (n=23), efficacy was again classed as excellent for all patients. Mean MCF increased by 4.83±0.98 mm from baseline to 1 h after first infusion (7.06±3.36 mm in adults). There were no related serious adverse events, severe allergic, hypersensitivity reactions, or thromboembolic events, and no inhibitory anti-fibrinogen antibodies were detected.Conclusions: This analysis of data from two prospective studies demonstrated favorable efficacy, safety, and PK parameters of the new HFC in adolescents with afibrinogenemia. PK parameters were broadly comparable with those of the comparator HFC. After infusion of the new HFC, MCF increased statistically significantly and hemostatic efficacy was rated excellent in all patients. No safety concerns relating to the new HFC were identified in these study patients. [Display omitted] DisclosuresPeyvandi:Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria. Schwartz:Octapharma US: Employment. Knaub:Octapharma AG: Employment.

Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency

Background Human fibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a-/hypofibrinogenemia. Objectives To assess pharmacokinetics (PK), effects on thromboelastometry maximum clot firmness (MCF), and safety of a new double virus-inactivated/eliminated, highly purified HFC vs. active control. Patients/Methods In this multinational, randomized, phase II, open-label, crossover study in 22 congenital afibrinogenemia patients aged ≥12years, 70mgkg-1 of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan® P/RiaSTAP™, CSL Behring GmbH) were administered, followed by crossover to the other concentrate. Fibrinogen activity, PK and MCF in plasma were assessed. Results The concentrates were not bioequivalent for the primary endpoint, AUCnorm (mean ratio, 1.196; 90% confidence interval [CI], 1.117, 1.281). Remaining PK parameters (Cmaxnorm , IVR, t1/2 , MRT) reflected bioequivalence between concentrates, except for clearance (mean ratio, 0.836; 90% CI, 0.781, 0.895) and Vss (mean ratio, 0.886; 90% CI, 0.791, 0.994). Mean AUCnorm was significantly larger for the new HFC (1.62±0.45 vs. 1.38±0.47hkggL-1 mg-1 , P=0.0001) and mean clearance was significantly slower (0.665±0.197 vs. 0.804±0.255mLh-1 kg-1 , P=0.0002). Mean MCF increased from 0mm to 9.68mm (new HFC) and 10.00mm (control) 1-hour post-infusion (mean difference, -0.32mm; 95% CI, -1.70, 1.07, n.s.). No deaths, thromboses, viral seroconversions or serious related adverse events occurred. Conclusions Bioequivalence was not demonstrated for AUCnorm , clearance and Vss . Larger AUCnorm and slower clearance were observed for the new HFC. Remaining pharmacokinetic parameters reflected bioequivalence to control. Safety profiles and increases in clot strength were comparable between concentrates.

Biochemical characterization, stability, and pathogen safety of a new fibrinogen concentrate (fibryga®)

Fibryga® is a new lyophilized fibrinogen concentrate for intravenous use for the treatment of congenital fibrinogen deficiency. fibryga® is produced from pooled human plasma and the final product is characterized by high purity, integrity, and pathogen safety.Functional activity of fibrinogen was demonstrated by cross-linking studies and thromboelastometry; integrity of the fibrinogen molecule was demonstrated by size exclusion chromatography and the detection of only trace amounts of activation markers in the final product.Pathogen safety of fibryga® was proved by downscaling studies for the two dedicated pathogen inactivation/removal steps, i.e. solvent detergent treatment and nanofiltration.Fibryga® is stable for at least three years when stored at room temperature.In conclusion, the performed studies demonstrated that fibryga® meets the requirements for a state-of-the-art fibrinogen concentrate, such as a satisfactory activity profile combined with a favorable pathogen safety profile and stability.

Identification of novel mutations in congenital afibrinogenemia patients and molecular modeling of missense mutations in Pakistani population

BackgroundCongenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder that was first described in 1920. It is transmitted as an autosomal recessive trait that is characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan and its neighboring countries has resulted in a higher number of cases of congenital fibrinogen deficiency in their respective populations. This study focused on the detection of mutations in fibrinogen genes using DNA sequencing and molecular modeling of missense mutations in all three genes [Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG)] in Pakistani patients.MethodsThis descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of Helsinki. Patients with fibrinogen deficiency were screened for mutations in the Fibrinogen alpha (FGA), beta (FGB) and gamma (FGG) genes by direct sequencing. Molecular modeling was performed to predict the putative structure functional impact of the missense mutations identified in this study.ResultsTen patients had mutations in FGA followed by three mutations in FGB and three mutations in FGG, respectively. Twelve of these mutations were novel. The missense mutations were predicted to result in a loss of stability because they break ordered regions and cause clashes in the hydrophobic core of the protein.ConclusionsCongenital afibrinogenemia is a rapidly growing problem in regions where consanguinity is frequently practiced. This study illustrates that mutations in FGA are relatively more common in Pakistani patients and molecular modeling of the missense mutations has shown damaging protein structures which has profounding effect on phenotypic bleeding manifestations in these patients.

Fibrinogen deficiency in a dog - a case report

BackgroundAmong coagulation disorders, primary fibrinogen deficiency is very rare in dogs. It is divided into hypofibrinogenemia, afibrinogenemia and dysfibrinogenemia. Afibrinogenemia has been described in three dogs. There are, however, no published case reports of primary hypofibrinogenemia in dogs.Case presentationA 1.5 year-old male German Pointer dog was evaluated for a locked-jaw syndrome associated with eye protrusion which appeared after a minor head trauma. Three months before the trauma, a persistent increase in coagulation times was detected by the referring veterinarian after a strong suspicion of snake envenomation. Apart for the primary complaint, physical examination was normal. A complete hemostatic profile revealed a moderately increased prothrombin time, activated partial thromboplastin times and a dramatically decreased fibrinogen concentration (0.34 g/L, reference interval [1.3–4.8 g/L]). Platelet count, plasma D-dimers and antithrombin, were all within the reference intervals and not consistent with a disseminated intravascular coagulation. Other possible causes of hypofibrinogenemia such as chronic hemorrhage and liver failure were excluded by laboratory work-up and imaging studies. Finally, antifibrinogen circulating anticoagulants were excluded using a dilution of citrated plasma from the pooled plasma of healthy dogs. These results supported a diagnosis of congenital fibrinogen deficiency and secondary retrobulbar hematoma and/or cellulitis. The dog’s condition improved rapidly after symptomatic treatment with corticosteroids and antibiotics. At the 1 year follow-up, the dog was clinically normal but a persistent hypofibrinogenemia (≤ 0.8 g/L) remained.ConclusionsVarious clinical presentations may occur in canine primary hypofibrinogenemia which should be included in the list of coagulation disorders. Diagnosis should include fibrinogen determination by coagulometric and non-coagulometric methods to differentiate from dysfibrinogenemia. There is no specific treatment but care should be taken to prevent bleeding and trauma. Emergency management of bleeding episodes with cryoprecipitate is the treatment of choice.

Efficacy of Human Fibrinogen Concentrate for on-Demand Treatment of Acute Bleeding and to Prevent Bleeding during and after Surgery in Subjects with Congenital Fibrinogen Deficiency

Patients with congenital afibrinogenaemia and hypofibrinogenaemia, frequently experience severe bleeding episodes starting already at birth or during early childhood. Bleeding may occur after a minor trauma or a surgical intervention into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate (HFC) corrects the haemostatic defect and arrests bleeding in these patients. Octafibrin (Octapharma OPG, Vienna, Austria) is a plasma-derived, highly purified, lyophilized fibrinogen concentrate with two dedicated virus inactivation/removal steps was used in this study.This study was prospective, open-label and multinational, in adult and adolescent a- or hypofibrinogenemic patients, to investigate the safety and efficacy of Octafibrin a new HFC in the treatment of on-demand bleeding (BE) and surgical prophylaxis.A planned interim analysis comprises data of 11 adult and 2 adolescent patients. Efficacy was assessed using a 4 point objective scale completed by the investigator and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) for each bleeding or surgical episode.Eleven of the 13 patients experienced a total of 23 minor BEs. Sixteen BEs (69.6%) were spontaneous and 7 (30.4%) were traumatic. A majority of BEs (21/23) required one HFC infusion (91.3%) and 2 (8.7%) BEs required two infusions. The median (range) dose of HFCadministered for the treatment of all BEs was 57.5 mg/kg (33.9-71.4 mg/kg) per infusion and 58.8 mg/kg (33.9-101.7 mg/kg) per BE.The success rate (efficacy rating of excellent or good) for all BEs was 100% (90% CI: 0.88, 1.00) as adjudicated by the IDMEAC (all excellent).Maximum clot firmness (MCF) using thromboelastometry (ROTEM®) performed in plasma was also determined for the first infusions administered for the treatment of all 23 BEs in the 11 BE patients. The mean (±SD) change in MCF from baseline (MCF 0) to 1 hour after the first infusion of HFCwas 6.5 mm (±2.0) (95% CI: 5.65, 7.40; p<0.0001). This significant overall increase in MCF from baseline coincided with the 100% haemostatic efficacy for all BEs.Four patients underwent 4 surgeries (3 major 1 minor, two of these patients were treated for both BE and surgery). The post-operative success rate (haemostatic efficacy excellent or good) was 100% (90% CI 0.5, 1.0), as assessed by the investigator and the IDMEAC.There have been no reports of serious adverse events related to the infusion of the HFC.In conclusion this study showed 100% hemostatic efficacy in on-demand treatment with HFC in bleeding patients with congenital fibrinogen deficiency. Also hemostatic efficacy in surgical prophylaxis in 4 patients was rated excellent/good. Maximum clot firmness values showed a statistically significant increase from baseline to 1 hour post-infusion in all patients after HFCadministrations reflecting the successful treatment of bleeding events. There were no related serious adverse events, no thromboembolic events, no allergic or severe hypersensitivity reactions, and no anti-fibrinogen antibodies that developed during the study. DisclosuresSchwartz:Octapharma: Employment. Knaub:Octapharma: Employment. Peyvandi:Bayer: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; CSL Behring: Speakers Bureau; Grifols: Speakers Bureau; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; SOBI: Speakers Bureau.

Identification of Novel Mutations with Molecular Modelling of Missense Mutations of Congenital Afibrinogenemia Patients in Pakistan

Background:Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder which was first described in 1920. It is transmitted as an autosomal recessive trait characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan and its neighboring countries has resulted in higher cases of congenital fibrinogen deficiency in their respective populations.Aims: This study focuses on the detection of mutations in the fibrinogen genes by DNA sequencing and molecular modeling of missense mutations in all three genes (Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) in Pakistani patients.Methods:This descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of Helsinki. Patients with fibrinogen deficiency (tested by Fibrinogen functional assay from Laboratoire Stago, Asnieres, France) were screened for mutations in the Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) genes by direct sequencing. Molecular modeling was performed to predict the putative structure functional impact of the missense mutations identified in this studyResults:Ten patients had FGA mutations, four have FGB mutations and one mutation was detected in FGG. Thirteen of these mutations were novel. The missense mutations are predicted to result in loss of stability since they (a) break ordered regions (b) cause clashes in the hydrophobic core of the protein.Conclusion:Congenital afibrinogenemia is a rapid growing problem in countries such as Pakistan where consanguinity is frequently practiced. This study illustrates the fact that mutations in FGA are relatively more common in our population than those in FGB where as FGG mutations appear rarer. DisclosuresOldenburg:SOBI: Consultancy.

Pharmacokinetic (PK) Comparison of Two Fibrinogen Concentrates for the Treatment of Congenital Fibrinogen Deficiency

Patients with congenital afibrinogenaemia and hypofibrinogenaemia, experience frequent severe bleeding episodes starting at birth or early childhood. Bleeding may occur after a minor trauma or a small surgical intervention, into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate can correct the haemostatic defect and arrest the bleeding in patients with these fibrinogen deficiencies. Octafibrin is plasma derived, highly purified, lyophilized, fibrinogen concentrate, which has been double virus safeguarded using two dedicated virus inactivation/removal steps. In this study, the (PK) profile of this new concentrate is compared to a commercially available product (Haemocomplettan® P/RiaSTAPTM). This ongoing study is a prospective, randomized, open-label, multinational, crossover PK comparison of Octafibrin to an existing marketed product with planned interim data in 9 adult and adolescent patients, including comparison of a surrogate efficacy endpoint Maximum Clot Firmness (MCF) measured by ROTEM®. The study includes a crossover design where both products are given a single dose in a randomized fashion separated by an observation period and washout of any fibrinogen product prior to infusion. Patients are confirmed afibrinogenemic with baseline fibrinogen activity plasma level of &lt; 0.20. All fibrinogen and MCF testing was performed in a central lab using validated methods. Nine patients completed the study until the end of May 2014. There have been no reports of adverse events (AE) related to the infusion of this novel concentrate. Comparable PK profiles between the products were seen but in key parameters, Normalized Aria Under the Curve (AUCnorm) (h·mg/mL/(mg/kg) Octafibrin 0.994, Haemocomplettan® P/RiaSTAPTM 0.731 p-value 0.014) and clearance (mL/h/kg Octafibrin 0.522, Haemocomplettan® P/RiaSTAPTM 0.594 p-value 0.033), significant differences were observed between the groups. Comparable haemostatic efficacy of Octafibrin and Haemocomplettan® P/RiaSTAPTM was demonstrated based on their ability to significantly increase MCF. Mean (± SD) Fibrinogen Levels (g/L) during PK Assessment after Octafibrin and Haemocomplettan® P/RiaSTAPTM Administration, Standardized to 70 mg/kg (PK Population, n=9) Figure 1 Figure 1. Ratios of Octafibrin Relative to Haemocomplettan® P/RiaSTAPTM for AUC and AUCnorm (PK Population, N=9) Table 1 Baseline Characteristics of Patients with and without Cardiac Complications in TTP Fibrinogen activity Parameter ratio Mean 90% CI of mean ratio p-value AUC 139.11 79.25, 246.13 0.0173 AUCnorm 139.96 80.26, 245.94 0.0144 In conclusion, this study showed in general a comparable PK profile for Octafibrin and Haemocomplettan® P/RiaSTAPTM in patients with congenital fibrinogen deficiency. Octafibrin showed a significantly higher AUCnorm and lower clearance than the comparator. The haemostatic efficacy of Octafibrin, as measured by change in MCF as a surrogate parameter, was similar to that of the licensed comparator used in this study, and there was no related AE or SAE for Octafibrin after single-dose administration. Disclosures Schwartz: Octapharma: Employment. Knaub:Octapharma: Employment.