Prospective Evaluation of Bleeding Incidence in Fibrinogen Deficiency (PRO-RBDD Study)

BACKGROUND: Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenaemia) or both (hypodysfibrinogenaemia) of fibrinogen. Afibrinogenemia is associated with mild-to-severe bleeding, whereas hypofibrinogenemia is most often asymptomatic. Previously, our group (Peyvandi et al, JTH 2006) showed that in a group of 100 patients with afibrinogenemia and hypofibrinogenemia, the mean annual incidence of bleeding episodes was 0.7 on on-demand therapy (range 0-16.5) and 0.5 on prophylactic replacement therapy (range 0-2.6). Dys- and hypodysfibrinogenemia are commonly associated with bleeding, thrombosis, or both; however, most individuals are asymptomatic. Treatment of fibrinogen deficiency is challenging because the minimum amount of fibrinogen to prevent bleeding is unknown and because thromboembolism may occur in association with fibrinogen substitution therapy. Therefore a guideline for optimal treatment is not available yet. AIMS: The 3-year observational prospective study on rare bleeding disorders (PRO-RBDD) aimed at evaluating the incidence of bleeding episodes in patients with fibrinogen deficiency and the benefits and complication of current treatment regimens. METHODS: 17 Hemophilia Treatment Centers worldwide collected data in a web-based database at baseline (patient history) and at pre-specified time-points (every 6 months, follow up study); 146 patients (86 females/60 males) were recorded. Analysis was carried out on patients with available data on both antigen and activity levels. Bleeding incidence was calculated to evaluate number of bleeding episodes in patients on on-demand therapy. A survival analysis was also made to evaluate the cumulative incidence of the first bleeding requiring replacement therapy. Analysis was done using R v.3.3.1 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Data on activity and antigen level were available on 96 patients (54 females/42 males), of whom 81 are currently on follow up. Twenty-one (26%) patients were afibrinogenemic, 17 (21%) hypofibrinogenemic, 36 (44%) dysfibrinogenemic and 7 hypodysfibrinogenemic (9%), according to standard classification. Patients were followed up for a median of 810 days (IQR: 728-916, min-max: 221-1215). In on-demand therapy, the bleeding incidence was 0.86 patient-year -1 (95%CI 0.57-1.15) in afibrinogenemia, 0.30 (95%CI 0.15-0.52) in hypofibrinogenemia, 0.14 (95%CI 0.06-0.25) in dysfibrinogenemia and 0.06 (95%CI 0.-0.27) in hypodysfibrinogenemia. At 1200 days of follow up, the bleeding cumulative incidence of the first bleeding treated with replacement therapy was 0.43 (95%CI 0.11-0.64) in afibrinogenemia, 0.30 (95%CI 0.05-0.49) in hypofibrinogenemia, 0.06 (95%CI 0.0-0.14) in dysfibrinogenemia and 0.14 (95%CI 0.0-0.37) in hypodysfibrinogenemia. Prophylaxis regimen (dosage range 50 - 666 mg/Kg/month) with fibrinogen concentrate was used only in one third of patients (6/21) with afibrinogenemia and it seems to reduce the median number of bleeding events per year [from 1 (min-max: 1-3/year) to 0.4 (min-max: 0-1.25)]. Only one allergic reaction and no thrombotic events were reported. CONCLUSION: The results of this prospective observational study on patients with fibrinogen deficiency showed that the bleeding incidence decreased accordingly to plasmatic fibrinogen levels. Preliminary data on a limited number of patients with afibrinogenemia showed a reduction of bleeding episodes even if a wide range of prophylaxis dosage has been used. A larger group of patients and a longer follow up period are required to evaluate the efficacy of prophylaxis and to find the optimal target level to prevent spontaneous major bleeding in afibrinogenemic patients. Disclosures Palla: Pfizer: Other: travel support . Menegatti: Pfizer: Other: travel support . Blatny: CSL Behring: Speakers Bureau. Halimeh: Bayer Healthcare GmbH: Research Funding, Speakers Bureau; Baxalta Innovations GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; CSL Behring GmbH: Research Funding, Speakers Bureau; Novartis Pharma GmbH: Speakers Bureau; Novo Nordisk Pharma GmbH: Research Funding, Speakers Bureau; Octapharma GmbH: Research Funding, Speakers Bureau; LFB GmbH: Speakers Bureau; Pfizer Pharma GmbH: Research Funding, Speakers Bureau. Siboni: LFB: Speakers Bureau; Bayer: Speakers Bureau. Laros-Van Gorkom: Baxter: Research Funding; CSL Behring: Research Funding; Sanquin: Speakers Bureau. Schutgens: CSL Behring: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta: Research Funding; Novonordisk: Research Funding. De Moerloose: Bayer: Consultancy, Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding, Speakers Bureau; LFB: Speakers Bureau; Stago: Speakers Bureau; Novonordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Research Funding. Casini: CSL Berhing: Speakers Bureau; Bayer: Other: Travel support. Makris: CSL Behring: Consultancy; Novo Nordisk: Consultancy; Freeline Therapeutics: Consultancy; Bayer: Speakers Bureau; Biogen: Speakers Bureau; Grifols: Speakers Bureau. Chapin: Baxalta: Consultancy; CSL Behring: Consultancy; Novo Nordirsk: Consultancy; Alexion Pharmaceuticals: Consultancy; Apopharma: Consultancy; Bayer: Consultancy. Peyvandi: CSL Behring: Speakers Bureau; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity9s Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; Grifols: Speakers Bureau; SOBI: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Bayer: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau.