In this video lecture, Dr. Alessandro Casini discusses:
- The diagnostic approach to quantitative and qualitative hereditary fibrinogen disorders using fibrinogen activity, antigen, and genetic testing.
- How fibrinogen level, genotype, and clot properties contribute to heterogeneous bleeding, thrombotic, and obstetric phenotypes.
- Individualized management with fibrinogen replacement, antifibrinolytics, thromboprophylaxis, and special considerations for surgery and pregnancy.
Professor Alessandro Casini is an Associate Professor at the Faculty of Medicine, University of Geneva, and a senior attending physician in the Division of Angiology and Hemostasis at the University Hospitals of Geneva. His clinical and research interests focus on rare bleeding disorders, with a particular emphasis on hereditary fibrinogen disorders, including their genetics, diagnosis, fibrin clot properties, and bleeding and thrombotic risk. He has contributed to international guidelines and collaborative research in the field and is actively involved in several national and international working groups on rare bleeding disorders. He is also President of the International Fibrinogen Physicians and Patients Association.
(Video Lecture Summary)
Introduction
Dr. Alessandro Casini reviews hereditary fibrinogen disorders, focusing on their diagnosis, clinical features, and management. These disorders include quantitative deficiencies, such as afibrinogenemia and hypofibrinogenemia, and qualitative deficiencies, including dysfibrinogenemia and hypodysfibrinogenemia. Their classification reflects fibrinogen levels, clinical characteristics, and genotype.
When to Suspect a Hereditary Fibrinogen Disorder
A hereditary fibrinogen disorder may be identified after an incidental finding of low fibrinogen, during investigation of bleeding or thrombosis, in patients with obstetric complications, or through family history and screening. Before diagnosing a hereditary disorder, acquired causes must be excluded. Dr. Casini discusses reduced fibrinogen synthesis, increased consumption, and acquired alterations in fibrinogen function. Examples include liver disease, disseminated intravascular coagulation, medications, and autoimmune disease.
Laboratory Diagnosis
Diagnosis follows a multistep approach beginning with PT, APTT, and functional fibrinogen measurement using the Clauss method. When fibrinogen activity is reduced, fibrinogen antigen should also be measured. Undetectable activity and antigen suggest afibrinogenemia. Reduced activity and antigen suggest hypofibrinogenemia or hypodysfibrinogenemia. Reduced activity with a normal antigen level suggests dysfibrinogenemia. Genetic testing can then help confirm the diagnosis.
Additional Laboratory Testing and Diagnostic Pitfalls
The most important laboratory measurements are fibrinogen function and quantity. The Clauss assay assesses fibrinogen activity, while immunoassays measure fibrinogen antigen. Additional tests include PT-derived fibrinogen, thrombin time, reptilase time, Clauss clot waveform analysis, and viscoelastic assays.
Dr. Casini highlights several diagnostic limitations. Fibrinogen antigen assays are not universally available, making it difficult to distinguish hypofibrinogenemia from dysfibrinogenemia or hypodysfibrinogenemia. Assay results can also vary according to the fibrinogen variant, reagent, and analyzer. At very low fibrinogen levels, laboratory detection limits may make severe hypofibrinogenemia difficult to distinguish from afibrinogenemia. PT-derived fibrinogen is not a functional measurement and can overestimate fibrinogen in dysfibrinogenemia.
Genetics of Fibrinogen Disorders
Fibrinogen consists of alpha, beta, and gamma chains encoded by FGA, FGB, and FGG. Variants affecting synthesis, assembly within the hepatocyte endoplasmic reticulum, or secretion into the circulation can result in quantitative deficiencies. Variants that alter the structure or function of the fibrinogen molecule can produce qualitative disorders. Hundreds of fibrinogen variants have been identified, including recurrent variants and regional clusters. Genetic testing can confirm the diagnosis, refine classification, support family screening and prenatal diagnosis, and in selected disorders provide information about the expected clinical phenotype.
Genotype-Phenotype Associations
Dr. Casini highlights fibrinogen storage disease as one example of a strong genotype-phenotype relationship. Variants lead to fibrinogen retention and aggregation within the hepatocyte endoplasmic reticulum, producing hypofibrinogenemia and liver disease. Liver histology can demonstrate fibrinogen accumulation within hepatocytes.
He also discusses thrombotic-related dysfibrinogenemia, in which particular variants are associated with thrombosis. However, individuals within the same family carrying the same fibrinogen variant may have different clinical manifestations. Other genetic modifiers and imbalances in hemostatic factors may influence the resulting phenotype.
Clinical Spectrum
Hereditary fibrinogen disorders have highly heterogeneous clinical presentations. Afibrinogenemia is the most severe deficiency and is associated with a high risk of bleeding as well as thrombosis. Patients with severe hypofibrinogenemia also have increased bleeding and thrombotic risks, while patients with mild or moderate hypofibrinogenemia are often asymptomatic.
In dysfibrinogenemia, many patients are asymptomatic or experience mild mucocutaneous bleeding, while some have a substantial thrombotic risk. Clinical phenotype therefore varies considerably across both quantitative and qualitative fibrinogen disorders.
Bleeding Risk
In quantitative fibrinogen disorders, bleeding risk is related to fibrinogen level. Patients with levels above 1 g/L are often asymptomatic, while levels below 0.5 g/L are frequently associated with spontaneous major bleeding. Patients with afibrinogenemia have the most severe bleeding phenotype and may experience hemarthrosis, muscular hematomas, central nervous system bleeding, heavy menstrual bleeding, and surgical bleeding.
In dysfibrinogenemia, fibrinogen level does not explain the bleeding phenotype. Patients are frequently asymptomatic or experience mild mucocutaneous bleeding, although major hemorrhage can occur. Women have a particularly important bleeding risk because of postpartum hemorrhage.
Thrombotic Risk
Hereditary fibrinogen disorders can also cause thrombosis. Dr. Casini notes that thrombosis has been reported in up to 15% of patients in several series. Proposed mechanisms include altered fibrin clot strength and permeability, abnormal thrombin-fibrin interactions, impaired fibrinolysis, and defective clot retraction.
This coexistence of bleeding and thrombotic risk is an important consideration when developing an individualized treatment plan.
Pregnancy and Obstetric Risk
Pregnancy is a high-risk clinical setting in hereditary fibrinogen disorders. Miscarriage has been reported in approximately 25% to 36% of pregnancies, while women with afibrinogenemia or hypofibrinogenemia are particularly susceptible to retroplacental hematoma. Postpartum hemorrhage is also frequent, particularly among women with a previous bleeding phenotype.
These risks require careful planning throughout pregnancy, delivery, and the postpartum period.
Fibrinogen Replacement
Available sources of fibrinogen include fibrinogen concentrate, cryoprecipitate, and fresh frozen plasma. Dr. Casini identifies fibrinogen concentrate as the preferred option because it provides a predictable increase in fibrinogen, does not contain additional coagulation factors, requires a small reconstitution volume, and does not carry an infectious risk.
Dosing should be individualized according to body weight, plasma volume, and product recovery. Access remains an important limitation because fibrinogen concentrate is unavailable or difficult to obtain in many countries where severe fibrinogen disorders are more prevalent.
Individualizing Treatment
Because evidence-based recommendations are limited, Dr. Casini emphasizes shared decision-making. Management should account for the biological profile, fibrinogen level, underlying variant, availability of concentrate, feasibility of venous access, and catheter-related thrombosis. Clinical factors are equally important, including personal and family histories of bleeding and thrombosis, quality of life, treatment burden, lifestyle, pregnancy, upcoming procedures, and the patient’s individual goals.
Management of Acute Bleeding and Surgery
For acute bleeding in severe fibrinogen deficiency, fibrinogen replacement is used to achieve a peak activity above 1.0 g/L, with subsequent dosing guided by clinical evolution and a trough target above 0.5 g/L. In mild disorders and some forms of dysfibrinogenemia, local or systemic antifibrinolytic therapy may be sufficient for minor mucosal bleeding.
For surgery in severe deficiency, Dr. Casini describes fibrinogen supplementation for both minor and major procedures, targeting a peak activity above 1.5 g/L. In milder hypofibrinogenemia or dysfibrinogenemia, supplementation is used for major surgery, while antifibrinolytics may be sufficient for minor procedures. A history of bleeding may justify replacement before minor surgery. Postoperatively, fibrinogen is maintained because of its role in wound healing, while mechanical or pharmacologic thromboprophylaxis should also be considered because these patients remain at risk of thrombosis.
Management of Thrombosis
Management of thrombosis depends on the type of fibrinogen disorder. In afibrinogenemia or severe hypofibrinogenemia, Dr. Casini discusses limited-duration anticoagulation accompanied by fibrinogen supplementation. In mild or moderate hypofibrinogenemia and some forms of dysfibrinogenemia, anticoagulation may be given without fibrinogen supplementation. For thrombotic-related dysfibrinogenemia, long-term anticoagulation is important, along with careful consideration of thromboprophylaxis during situations that increase thrombotic risk.
Pregnancy, Delivery, and Heavy Menstrual Bleeding
In women with afibrinogenemia or severe hypofibrinogenemia, fibrinogen supplementation should begin as early as possible in pregnancy. Replacement is also used around delivery, followed by careful postpartum monitoring because of the risk of hemorrhage. Management of milder disorders and dysfibrinogenemia depends on previous clinical symptoms and obstetric complications. Fibrinogen supplementation may be considered at delivery and in women with a previous bleeding phenotype or postpartum hemorrhage. For heavy menstrual bleeding, severe quantitative deficiency may require fibrinogen replacement during menstruation, while tranexamic acid is often sufficient in moderate or mild hypofibrinogenemia or dysfibrinogenemia. Dr. Casini also discusses hormonal therapy to reduce the risk of hemorrhagic ovarian cyst rupture.
Conclusion
Dr. Casini concludes that hereditary fibrinogen disorders are a heterogeneous group of diseases associated with distinct bleeding and thrombotic risks. Diagnosis requires assessment of fibrinogen activity and antigen, with genetic testing used to confirm and further classify the disorder.
In quantitative deficiencies, bleeding risk is related to fibrinogen level, while the phenotype of qualitative disorders reflects the properties of the abnormal fibrin clot. Fibrinogen replacement remains a cornerstone of treatment, but thrombotic risk persists and must be incorporated into management decisions. Care should therefore be personalized, with multidisciplinary management particularly important for pregnancy, postpartum bleeding, and heavy menstrual bleeding.