Clinical, Laboratory, and Molecular Aspects of Congenital Fibrinogen Disorders.

Congenital fibrinogen disorders (CFDs) include afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia. The fibrinogen levels, the clinical features, and the genotype define several sub-types, each with specific biological and clinical issues. The diagnosis of CFDs is based on the measurement of activity and antigen fibrinogen levels as well as on the genotype. While relatively easy in quantitative fibrinogen disorders, the diagnosis can be more challenging in qualitative fibrinogen disorders depending on the reagents and methods used, and the underlying fibrinogen variants. Overall, quantitative and qualitative fibrinogen defects lead to a decrease in clottability, and usually in a bleeding tendency. The severity of the bleeding phenotype is moreover related to the concentration of fibrinogen. Paradoxically, patients with CFDs are also at risk of thrombotic events. The impact of the causative mutation on the structure and the fibrinogen level is one of the determinants of the thrombotic profile. Given the major role of fibrinogen in pregnancy, women with CFDs are particularly at risk of obstetrical adverse outcomes. The study of the fibrin clot properties can help to define the impact of fibrinogen disorders on the fibrin network. The development of next generation sequencing now allows the identification of genetic modifiers able to influence the global hemostasis balance in CFDs. Their integration in the assessment of the patient risk on an individual scale is an important step toward precision medicine in patients with such a heterogeneous clinical course.

One Hundred Years of Congenital Fibrinogen Disorders.

Congenital fibrinogen disorders encompass a broad range of fibrinogen defects characterized by a wide molecular and clinical spectrum. From the first clinical description of afibrinogenemia in 1920, many major achievements have contributed to a better understanding of these complex disorders. The finding of causative mutations in all three fibrinogen genes has contributed to reveal the molecular mechanisms involved in biosynthesis of the fibrinogen molecule and to clarify the basic processes of fibrin polymerization and fibrinolysis. The compilation of abundant cases with detailed genetic, biological, and clinical features has enabled the classification of congenital fibrinogen disorders into several types and subtypes. Thus, the recent classification of congenital fibrinogen disorder is based not only on the clottable and antigenic fibrinogen levels but also on the patient's clinical phenotype and genotype. Fibrinogen supplementation is the cornerstone of bleeding management in fibrinogen disorders. Since the discovery of blood fractionation, the method of production of fibrinogen concentrate has been progressively modified to significantly improve purity and safety. Nevertheless, the availability of such products is still limited to a few countries and the optimal threshold of fibrinogen to target is still not established. In this review, we describe the major advances that have characterized 100 years of congenital fibrinogen disorders, focusing on afibrinogenemia and dysfibrinogenemia.

New Inhibitors in the Ageing Population: A Retrospective, Observational, Cohort Study of New Inhibitors in Older People with Hemophilia.

INTRODUCTION: A second peak of inhibitors has been reported in patients with severe hemophilia A (HA) aged >50 years in the United Kingdom. The reason for this suggested breakdown of tolerance in the aging population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on hemophilia B (HB) have ever been reported. AIM: The ADVANCE Working Group investigated the incidence of late-onset inhibitors and the use of prophylaxis in patients with HA and HB aged ≥40 years. METHODS: A retrospective, observational, cohort, survey-based study of all patients aged ≥40 years with HA or HB treated at an ADVANCE hemophilia treatment center. RESULTS: Information on 3,095 people aged ≥40 years with HA or HB was collected. Of the 2,562 patients with severe HA, the majority (73% across all age groups) received prophylaxis. In patients with severe HA, the inhibitor incidence per 1,000 treatment years was 2.37 (age 40-49), 1.25 (age 50-59), and 1.45 (age 60 + ). Overall, the inhibitor incidence was greatest in those with moderate HA (5.77 [age 40-49], 6.59 [age 50-59], and 4.69 [age 60 + ]) and the majority of inhibitor cases were preceded by a potential immune system challenge. No inhibitors in patients with HB were reported. CONCLUSION: Our data do not identify a second peak of inhibitor development in older patients with hemophilia. Prophylaxis may be beneficial in older patients with severe, and possibly moderate HA, to retain a tolerant state at a higher age.