Prospective Data Collection on Patients with Fibrinogen and Factor XIII Deficiencies: Prelimary Results of the PRO-RBDD Project
Authors: Peyvandi Flora , Menegatti Marzia , Palla Roberta , Siboni Simona Maria , Boscarino Marco , Susan Halimeh , Borhany Munira , Naveena Fatima , Pergantou Helen , Platokouki Helen , van Meegeren Monique , Brons Paul , Laros-van Gorkom Britta , Heiman Meadow , Shapiro Amy D , Bidlingmaier Christoph , Casini Alessandro , Saracevic Marko , Danijela Mikovic , Ozdemir Nihal , Mumford Andrew D , Fraustina Hsu , Chapin John C. , Harvey Andrew , Naderi Majid , Giansily Muriel , Schved Jean-Francois , de Moerloose Philippe 
Published: November 2019

Abstract

The PRO-RBDD is a prospective study of fibrinogen and FXIII deficiency designed to collect data on demographics, laboratory phenotype, genotype, clinical manifestations, obstetric data, surgery, treatment type and its efficacy and safety. Central laboratory testing is also available for diagnosis confirmation and genotyping. The aims of the study are to evaluate the prevalence of bleeding episodes, establish the minimum coagulant activity level to prevent bleeding (spontaneous or post-traumatic), and to monitor patients’ therapeutic regimens (efficacy and complications).
The PRO-RBDD network involved 52 Hemophilia Treatment Centers (HTCs) worldwide for a predicted 380 and 573 patients with fibrinogen and FXIII deficiency, respectively. Data collection started in February 2013 and will continue for 3 years (baseline and 6 follow-up visits are planned). Clinical bleeding episodes were classified into four categories of severity relying on the location and potential clinical impact as well as spontaneity of bleeding. Statistical analysis was performed using chi-square. Linear regression analysis was used to explore the association between coagulation factor activity level and clinical bleeding severity, with the relationship between the two variables defined through the coefficient β.
Currently, 26 HTCs have obtained local ethical committee approval and 15 have started data entry for 89 and 109 fibrinogen and FXIII deficient patients, respectively. Demographic data showed a similar distribution between males and females with a median age of 21 years (range: 1-84) and 19 years (range: 3-71) for fibrinogen and FXIII deficiency respectively; 38% and 22% of fibrinogen and FXIII deficient patients, respectively, were children (<12 years). The Table reports the association between residual coagulant level (laboratory severity) and clinical bleeding severity for both patient groups (p<0.01). Linear regression confirmed this association (fibrinogen: β=-0.29, p<0.01; FXIII: β=-12.94, p<0.01). Patient age at diagnosis and the type of treatments utilized are also reported (Table). In 33 women with fibrinogen deficiency and 21 with FXIII deficiency, 10 (30%) and 2 (10%), respectively, had menorrhagia; 5 out of 27 pregnancies (18%) in women with fibrinogen deficiency, and 16 out of 26 pregnancies (61%) in women with FXIII deficiency, resulted in spontaneous abortion; bleeding during pregnancy was observed in only 3/21 (14%) FXIII deficient women (only 1 of whom was on prophylaxis).
Follow-up data are available for up to 500 days for 51 and 28 patients with fibrinogen and FXIII deficiencies, respectively. Three out of 6 patients with fibrinogen deficiency (50%) on prophylaxis (30-45 mg/kg/month fibrinogen concentrate), experienced bleeding, while no bleeding was observed for 39 of the 45 fibrinogen deficient patients treated on-demand. Of the 14 patients with FXIII deficiency not on prophylaxis, 2 (14%) had spontaneous bleeds. No bleeding was reported for patients with FXIII deficiency on prophylaxis. No thrombotic events were recorded for any patients.
Preliminary data from the PRO-RBDD study of patients with fibrinogen and FXIII deficiency confirmed a strong association between coagulant activity levels and clinical severity in both deficiencies, and the efficacy of prophylaxis in patients with FXIII deficiency. For fibrinogen deficiency, the optimal prophylactic treatment regimen requires further study.
Abstract 2838. Table Fibrinogen patients FXIII patients Laboratory severity Severe undetectable Moderate 0.1-1 g/L Mild >1 g/L Severe undetectable Moderate 5-30% Mild >30% Bleeding severity Asymptomatic (no documented bleeding episodes) 1 (1%) 16 (19%) 12 (14%) 0 0 9 (10%) Grade I (bleeding after trauma or drug ingestion) 1 (1%) 7 (8%) 4 (5%) 2 (2%) 3 (3%) 2 (2%) Grade II (spontaneous minor bleeding) 4 (5%) 4 (5%) 5 (6%) 1 (1%) 1 (1%) 1 (1%) Grade III (spontaneous major bleeding) 22 (26%) 9 (10%) 0 70 (74%) 6 (6%) 0 Age at diagnosis median (min,max) 1.5 (0,24) 9 (0,84) 29 (0,64) 5 (0,54) 7 (0,36) 30 (2,46) Treatment type On demand 17 (20%) 38 (43%) 21 (24%) 8 (8%) 8 (8%) 7 (7%) Prophylaxis 11 (13%) 0 0 67 (71%) 2 (2%) 4 (4%)

Disclosures
Peyvandi: Biotest: Research Funding; Baxter: speaker's fee Other; Bayer: speaker's fee Other; Grifols: speaker's fee, speaker's fee Other; LFB: speker's fee, speker's fee Other; CSL Behring: speaker's fee, speaker's fee Other; NovoNordisk: Research Funding, speaker's fee Other; Kedrion biopharma: Research Funding. Mumford:NovoNordisk: Consultancy, speaker fee Other.