Phenotype, genotype, and laboratory assessment of congenital fibrinogen disorders: Data from the Rare Bleeding disorders in the Netherlands study
Bauke Haisma a),b); Sanna R. Rijpma b),c); Marjon H. Cnossen d); Paul L. den Exter e); Ilmar C. Kruis f); Karina Meijer g); Laurens Nieuwenhuizen h); Nick van Es i),j); Joline L. Saes k); Nicole M.A. Blijlevens a); Waander L. van Heerde b),l); Saskia E.M. Schols a),b).
a) Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands
b) Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands
c) Department of Laboratory Medicine, Laboratory of Hematology, Radboud university medical center, Nijmegen, the Netherlands
d) Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands
e) Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
f) Netherlands Hemophilia Society, Nijkerk, the Netherlands
g) Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands
h) Department of Hematology, Maxima Medical Center, Eindhoven, the Netherlands
i) Department of Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
j) Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
k) Department of Benign Hematology, van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, the Netherlands
l) Enzyre BV, Noviotech Campus, Nijmegen, the Netherlands
Abstract
Introduction
Congenital fibrinogen disorders (CFDs), encompassing quantitative (hypo−/afibrinogenemia) and qualitative (dysfibrinogenemia) defects, can result in bleeding or thrombotic events. This study aimed to enhance understanding of the clinical and genetic characteristics of CFD patients.
Methods
The Dutch cross-sectional RBiN study included 47 CFD patients (median age 38, 55 % women), categorized into (hypo)dysfibrinogenemia, severe (<500 mg/L), moderate (500–1000 mg/L) and mild hypofibrinogenemia (1000–1800 mg/L) as well as carriers with pathogenic variants but normal fibrinogen levels (>1800 mg/L). Clinical assessments included bleeding phenotype, thrombosis history, fibrinogen activity and antigen levels, thrombin and plasmin generation assays and genotypic analysis.
Results
Patients with severe hypofibrinogenemia displayed the highest median ISTH-BAT score (16), followed by moderate hypofibrinogenemia (11), (hypo)dysfibrinogenemia (6), mild hypofibrinogenemia (4) and carriers (0). Female-specific bleeding (postpartum hemorrhage, heavy menstrual bleeding) was prevalent across all CFD subtypes, with moderate hypofibrinogenemia showing high average scores on these ISTH-BAT items (3.0 and 2.3). Postoperative bleeding was common in moderate and severe hypofibrinogenemia (average ISTH-BAT item scores of 2.5 and 2.8, respectively). Patients with biallelic variants had lower fibrinogen activity levels (median 200 mg/L) than those with monoallelic variants (935 mg/L, p < 0.001). Fibrinogen activity levels correlated positively with plasmin peak height (R = 0.74, p < 0.001) and inversely with thrombin potential (R = –0.55, p = 0.002). Thrombin potential was 1.77-fold higher in patients with a venous thrombosis history (n = 5, p = 0.03) than in healthy controls.
Conclusions
In patients with CFDs, postoperative bleeding correlates with fibrinogen activity, while female-specific bleeding affects all CFD subtypes. Elevated thrombin generation might explain thrombosis risk in these patients.