RARE DISEASE
Congenital fibrinogen deficiency
Congenital fibrinogen deficiency
Congenital fibrinogen deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Congenital fibrinogen deficiency encompasses rare inherited disorders of fibrinogen quantity (afibrinogenemia, hypofibrinogenemia) or function (dysfibrinogenemia), disrupting clot formation. Manifestations range from severe spontaneous bleeding (afibrinogenemia) to thrombosis (dysfibrinogenemia). Diagnosis involves prolonged clotting times (PT, aPTT), thrombin time, and fibrinogen assays [1][7][12]. Management prioritizes fibrinogen replacement (concentrates preferred), with tailored approaches for bleeding, surgery, or pregnancy [3][8][13].
Burden
Severe bleeding (hemarthrosis, intracranial hemorrhage) in afibrinogenemia; thrombosis risk in dysfibrinogenemia [1][6][16].
Obstetric complications (recurrent miscarriage, menorrhagia) and neonatal umbilical bleeding [4][12][16].
Mortality linked to untreated hemorrhage; long-term prognosis favorable with early diagnosis and therapy [1][8][20].
Therapies
Replacement: Fibrinogen concentrates (e.g., RiaSTAP®) for acute bleeding/prophylaxis; cryoprecipitate/FFP if unavailable [3][5][13].
Prophylaxis: Routinely recommended during pregnancy to prevent miscarriage [2][8][16].
Thrombosis management: Anticoagulation with concurrent fibrinogen replacement in high-risk cases [3][16].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
150 drug discovery papers about Congenital fibrinogen deficiency, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
150 drug discovery papers about Congenital fibrinogen deficiency, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-27 | Fibrinogen Concentrate in Acute Hemorrhage: Mechanistic Insight, Thresholds, and Targeted Replacement.
Fibrinogen is an essential component of hemostasis and clot formation that stabilizes the platelet-dependent primary hemostatic process. Low fibrinogen levels can be primary (congenital) or secondary (acquired). Acquired hypofibrinogenemia may result from chronic diseases (e.g., liver, autoimmune diseases, and malignancies) or major hemorrhage (e.g., trauma, surgery). Low fibrinogen levels are both a symptom and a precipitating factor for coagulopathy and ongoing bleeding. Fibrinogen repletion with fibrinogen-containing products is important for managing coagulopathic bleeding with suspected or documented hypofibrinogenemia. Different available fibrinogen sources include fibrinogen concentrate, cryoprecipitate, and frozen plasma and vary based on multiple factors including fibrinogen content, purity, other clotting or non-clotting proteins (e.g., immunomodulating proteins or proteins of unknown function), preparation time, safety, volumes, and availability. Fibrinogen replacement strategies have been studied in trauma but also in patients undergoing spine, cytoreductive, and cardiac surgery. In this review, we discuss the physiological actions of fibrinogen, strategies for control of coagulopathic bleeding related to hypofibrinogenemia, and the therapeutic, logistical, and economic factors that influence treatment decisions. In addition, current guidelines and clinical studies were considered regarding the formation of evidence-based treatment strategies that can be individualized at the patient's bedside.
2026-07-14 | Perianal Crohn Disease in a Patient With Congenital Afibrinogenemia: A Multidisciplinary Therapeutic Management Challenge.
Congenital afibrinogenemia is a rare autosomal recessive coagulation disorder characterized by absent or severely reduced circulating fibrinogen levels, leading to variable hemorrhagic manifestations. The coexistence of congenital afibrinogenemia and Crohn disease is exceptionally rare and represents a major diagnostic and therapeutic challenge, particularly in patients with active fistulizing perianal disease requiring repeated invasive procedures and immunosuppressive therapy. A 20-year-old woman with congenital afibrinogenemia diagnosed during childhood presented with chronic bloody diarrhea and perianal symptoms. Her bleeding history included umbilical cord bleeding, post-vaccination bleeding, recurrent ecchymoses, and fibrinogen levels below 0.4 IU/L. Seven months before admission, she developed a perianal abscess requiring surgical drainage, followed by persistent mucous and bloody diarrhea. Imaging demonstrated inflammatory rectal thickening and an active horseshoe anal fistula. Because of the anticipated hemorrhagic risk associated with endoscopic biopsies, intravenous fibrinogen concentrate was administered before endoscopy. The diagnosis of colonic Crohn disease with active fistulizing perianal involvement was established based on clinical, radiological, endoscopic, and histopathological findings. Following multidisciplinary evaluation, treatment with infliximab and azathioprine was initiated. During follow-up, recurrent epistaxis was successfully controlled with fibrinogen replacement therapy, while gastrointestinal and perianal symptoms markedly improved without major hemorrhagic, thrombotic, or infectious complications. This association of congenital afibrinogenemia with active fistulizing perianal Crohn disease highlights the complexity of balancing inflammatory control, procedural safety, and hemorrhagic risk. Individualized multidisciplinary management and appropriate peri-procedural hemostatic support are essential to optimize outcomes in this exceptionally rare clinical setting.
2026-06-24 | Comparative Biochemical and Functional Characterization of a Novel Human Fibrinogen Concentrate (BT524) and Established Plasma-Derived Fibrinogen Concentrates
Abstract Human fibrinogen concentrate is used as replacement therapy for congenital and acquired fibrinogen deficiencies. Despite similar manufacturing principles, compositional differences among products may affect clot quality and hemostatic efficacy. BT524 (Biotest) is a newly developed human fibrinogen concentrate with proven clinical safety and efficacy. The objective of this study was to compare the biochemical composition and in vitro functional characteristics of BT524 with those of two commercially available plasma-derived fibrinogen concentrates (Products I and II). Three independent batches of each human fibrinogen concentrate were analyzed for the total and clottable protein, fibrinogen antigen, fibrinogen activity by Clauss, clotting factors, degradation markers (fibrinopeptide A and D-dimer), sub-visible particles, and aggregates. Maximum clot firmness and dynamics were assessed using rotational thromboelastometry (fibrin-based thromboelastometry). Fibrinogen deficient plasma with low factor XIII content was spiked each fibrinogen concentrate and increasing concentrations of factor XIII (0–0.8 U/mL). BT524 showed consistent fibrinogen content but contained no active factor VIII, factor XIII, or von Willebrand factor, indicating a precisely defined composition. Levels of degradation markers, aggregates, and sub-visible particles were markedly lower than in comparator products, reflecting the superior biochemical purity of BT524. BT524 achieved significantly higher maximum clot firmness than Product I (p<0.0001) and demonstrated comparable performance with Product II. Spiking of factor XIII resulted in an additional increase in maximum clot firmness in BT524 and Product II, but not in Product I, proving functional factor XIII susceptibility of BT524. BT524 demonstrates high biochemical purity and robust functional clot formation. These findings highlight that fibrinogen concentrates differ in composition, functionality and molecular integrity, which determines clot quality and hemostatic performance.
2026-06-04 | Quantitative fibrinogen disorders: A retrospective study from a tertiary care centre in India.
Background and objectives Congenital fibrinogen disorders encompass both quantitative and qualitative abnormalities of fibrinogen, characterised by variable bleeding or thrombotic tendencies. Due to their rarity and varied presentations, delays in diagnosis are common, which can significantly impact patient outcomes. This study was conducted to describe the clinical and demographic profiles of patients with congenital quantitative fibrinogen disorders over a 20-year period (2003-2024) at a tertiary care centre. Methods A retrospective analysis was conducted using laboratory records to identify 17 patients with quantitative fibrinogen disorders, characterised by prolonged prothrombin time (PT), activated partial thromboplastin time (APTT), and undetectable or low fibrinogen levels. Only 10 out of 17 patients could be contacted for follow up. The clinical presentation, including scoring of bleeding symptoms using the International Society on Thrombosis and Haemostasis - Bleeding Assessment Tool (ISTH-BAT), as well as demographic variables such as age of onset, first visit to our hospital, and diagnostic delays, were recorded. Treatment and follow up data were recorded. Results Majority of patients showed symptoms in the neonatal period, with umbilical bleeding as the most common initial manifestation, followed by post-traumatic and cutaneous bleeding. Despite early symptom onset, a median diagnostic delay of four years was observed. Seven cases were under regular follow up with on-demand therapy. Three patients died during follow up. Most of the cases received fresh frozen plasma. Interpretation and conclusions This study describes the clinical profile of quantitative fibrinogen disorders and emphasises the importance of increased awareness, early diagnosis, and standardised management in these patients. Given the significant risk of bleeding, proactive measures such as patient education and close monitoring are crucial.
2026-04-28 | The use of fibrinogen concentrate in coagulation testing aids in the diagnosis and management of rare bleeding disorders.
Many clinical laboratories lack the methods or resources to quickly identify rare haemorrhagic diseases, such as genetic/acquired fibrinogen defects and factor XIII deficiency. This report explored the value of human fibrinogen concentrate in the diagnosis and management of rare bleeding disorders through three case studies. Case 1 involved acquired hypofibrinogenemia caused by snake bite, where the coagulation abnormality was corrected by adding fibrinogen in vitro, confirming the mechanism of snake venom-specific degradation of fibrinogen. Case 2 utilised fibrinogen solution to establish a thromboelastography mixing test for rapid diagnosis of autoimmune factor XIII inhibitors. Case 3 improved platelet aggregation function in patients with congenital abnormal fibrinogenaemia through fibrinogen solution. These case studies showed that fibrinogen concentrate may serve as a specific additive to assist in the rapid identification of coagulation dysfunction and guide precise treatment.
cell therapies
2024-07-03 | Budd-Chiari syndrome associated with congenital afibrinogenaemia reversed after orthotopic liver transplant.
A woman in her mid-20s, a known case of congenital afibrinogenaemia, presented with abdominal pain and distension. She was diagnosed with decompensated liver cirrhosis due to Budd-Chiari syndrome. She underwent deceased donor liver transplantation. Preoperatively, her serum fibrinogen level was undetectable and prothrombin time and international normalised ratio (INR) were unrecordable. Intraoperatively, she was given thromboelastography-guided human fibrinogen concentrate. Postoperatively, her fibrinogen, prothrombin time and INR normalised rapidly. This report summarises the rare occurrence of a complication of hypercoagulability (Budd-Chiari syndrome) in the setting of congenital hypocoagulability (congenital afibrinogenaemia). In this report, we discuss the simultaneous management of these two clinical problems and the curative role of liver transplantation.
2021-05-14 | Liver transplantation as a novel strategy for resolution of congenital afibrinogenemia in a pediatric patient.
Fibrinogen replacement therapy is a treatment mainstay for patients with afibrinogenemia and significant bleeding. A male infant with congenital afibrinogenemia and several spontaneous hemarthroses commenced cryoprecipitate prophylaxis but developed severe urticarial reactions. He transitioned to a human fibrinogen concentrate (HFC) (RiaSTAP® , CSL Behring; 70 mg/kg biweekly) but continued experiencing hemarthroses (estimated annualized bleeding rate [ABR]: 5-6) and severe anaphylactic reactions, despite pre- and postinfusion medications. Following switching to a new HFC (Fibryga® , Octapharma; 50 mg/kg biweekly), ABR was 0-1 with no further infusion reactions. Aged 9 years, because of limited quality of life, development of obesity and fatty liver disease, he underwent orthotopic liver transplant (OLT) under HFC coverage. Pharmacokinetic analysis guided presurgical fibrinogen levels > 150 mg/dL. No intraoperative HFC infusions were required. Coagulation profile and fibrinogen levels remained within normal limits during and posttransplant. To our knowledge, this is the first pediatric report of afibrinogenemia successfully treated with OLT.
2011-06-28 | Recurrent massive hemoperitoneum due to ovulation as a clinical sign in congenital afibrinogenemia.
Massive hemoperitoneum due to ovulation is a rare but serious and life-threatening complication for women with coagulation disorders, and may lead to surgical interventions and even oophorectomy. Congenital afibrinogenemia is an uncommon coagulation disorder usually discovered during childhood. Intraabdominal bleeding due to ovulation is very rare in these patients and only a few cases of corpus luteum rupture and hemoperitoneum in afibrinogenemic patients have been described. In all women, the diagnosis was known since childhood. We report on a 24-year-old woman with congenital afibrinogenemia with recurrent massive intraabdominal bleeding due to ovulation as the presenting clinical sign. Exploratory laparotomy and excision of the ruptured follicle was performed at the first bleeding episode; the second episode was managed with fresh frozen plasma and blood transfusions. Conservative management is crucial for these patients. If surgery cannot be avoided, a conservative surgical approach should be chosen to preserve ovarian function.
2008-04-01 | Manipulating the quality control pathway in transfected cells: low temperature allows rescue of secretion-defective fibrinogen mutants.
Congenital afibrinogenemia is characterized by the absence of fibrinogen, a hexamer composed of two copies of three polypeptides, Aalpha. Bbeta and gamma. The disease is caused by mutations in one of the three fibrinogen-encoding genes, FGA, FGB and FGG. Among these, several mutations have been reported to specifically impair fibrinogen secretion. We previously showed that secretion-defective fibrinogen mutants are retained in a pre-Golgi compartment and demonstrated the importance of the homologous betaC and gammaC domains in secretion. Here our aim was to restore the secretion of these mutants and study the properties of the rescued mutant molecules. COS-7 cells were transfected and incubated with chemical chaperones or at low temperature. Clotting assays and plasmin digestion studies were performed to characterize secreted fibrinogen molecules. The secretion defect of two missense mutants but not that of late-truncating mutants could be partially corrected by incubating cells at 27 degrees C. By contrast, exposure of cells to chemical chaperones i.e. 4-phenylbutyrate, dimethyl sulfoxide or trimethylamine N-oxide had no effect. The mutants rescued at 27 degrees C were incorporated into fibrin clots and formed factor XIII-mediated gamma-gamma dimers in contrast to the dysfibrinogenemia Vlissingen/Frankfurt IV mutant, a negative control for these assays. However, plasmin digestion analyses revealed aberrant patterns for the mutants compared to normal fibrinogen. Low temperature can restore the secretion of a subset of mutant fibrinogen molecules demonstrating that therapeutic manipulation of the quality control pathway is feasible for afibrinogenemia even though functional assays suggested a non-native conformation for the mutant molecules analyzed.
1985-09-06 | Congenital afibrinogenemia and recurrent early abortion: a case report.
The role of the fibrinogen molecule in the maintenance of normal pregnancy is not yet well understood; however, several cases have been previously reported in which failure to complete normal pregnancy was associated with either hypofibrinogenemia, dysfibrinogenemia, or deficiency in factor XIII (fibrin-stabilizing factor) which is important for the crosslinking of the fibrin. A case of congenital afibrinogenemia is described. The patient, a 22-yr-old woman, who suffered from a moderate hemorrhagic tendency associated with very low (less than 10 mg/dl) plasma fibrinogen levels, had three consecutive spontaneous abortions. In view of the previous cases reported, the question is raised whether patients with low or abnormal fibrinogen should be treated with plasma transfusions in order to maintain a normal pregnancy.
gene therapies
2022-02-01 | An FGA Frameshift Variant Associated with Afibrinogenemia in Dachshunds.
Congenital fibrinogen disorders are very rare in dogs. Cases of afibrinogenemia have been reported in Bernese Mountain, Bichon Frise, Cocker Spaniel, Collie, Lhasa Apso, Viszla, and St. Bernard dogs. In the present study, we examined four miniature wire-haired Dachshunds with afibrinogenemia and ascertained their pedigree. Homozygosity mapping and a genome-wide association study identified a candidate genomic region at 50,188,932-64,187,680 bp on CFA15 harboring FGB (fibrinogen beta chain), FGA (fibrinogen alpha chain), and FGG (fibrinogen gamma-B chain). Sanger sequencing of all three fibrinogen genes in two cases and validation of the FGA-associated mutation (FGA:g.6296delT, NC_006597.3:g.52240694delA, rs1152388481) in pedigree members showed a perfect co-segregation with afibrinogenemia-affected phenotypes, obligate carriers, and healthy animals. In addition, the rs1152388481 variant was validated in 393 Dachshunds and samples from 33 other dog breeds. The rs1152388481 variant is predicted to modify the protein sequence of both FGA transcripts (FGA201:p.Ile486Met and FGA-202:p.Ile555Met) leading to proteins truncated by 306 amino acids. The present data provide evidence for a novel FGA truncating frameshift mutation that is very likely to explain the cases of severe bleeding due to afibrinogenemia in a Dachshund family. This mutation has already been spread in Dachshunds through carriers before cases were ascertained. Genetic testing allows selective breeding to prevent afibrinogenemia-affected puppies in the future.
2015-10-15 | In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes.
Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bβ and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGA homozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality. To explore a targeted gene therapy approach for patients with congenital afibrinogenemia. At the time of transplant, the patient's FGA-deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα-chain. FGA-transduced hepatocytes produced fully functional fibrinogen in vitro. Orthotopic liver transplantation is a possible rescue treatment for failure of on-demand fibrinogen replacement therapy. In addition, we provide evidence that hepatocytes homozygous for a large FGA deletion can be genetically modified to restore Aα-chain protein expression and secrete a functional fibrinogen hexamer.
2001-08-02 | Fibrinogen gene mutations accounting for congenital afibrinogenemia.
This article reviews recent progress made in understanding the molecular basis of congenital afibrinogenemia, an autosomal recessive coagulation disorder characterized by the complete absence of detectable fibrinogen. We have identified the first causative mutations for this disorder in a non-consanguineous Swiss family; these were homozygous deletions of approximately 11 kb of the fibrinogen alpha chain (FGA) gene. Haplotype data implied that the deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. All the deletions were identical to the base pair, and probably resulted from non-homologous (illegitimate) recombination. In a subsequent study of 13 unrelated patients with congenital afibrinogenemia we analyzed the FGA gene in order to identify the causative mutations, and to determine the prevalence of the 11-kb FGA deletion. Although this deletion was found in an additional unrelated patient, the most common mutation was at the donor splice site of FGA intron 4 (IVS4 + 1 G > T). Three frameshift mutations, two nonsense mutations, and one other splice site mutation were also characterized. Other studies identified one further FGA nonsense mutation, two FGB missense mutations, and one FGG nonsense mutation, all in homozygosity in a single patient. In conclusion, the majority of patients have truncating mutations in the FGA gene although, intuitively, all three fibrinogen genes could be predicted to be equally implicated. These results will facilitate molecular diagnosis of the disorder, permit prenatal diagnosis for families who so desire, and pave the way for new therapeutic approaches such as gene therapy.
small molecules
2026-03-22 | Managing heavy menstrual bleeding in adolescents with bleeding disorders: Outcomes from a pragmatic LMIC approach.
Heavy menstrual bleeding (HMB) a common manifestation of bleeding disorders in adolescents contributes to anemia, transfusions, and impaired quality-of-life (QOL). Evidence supporting practical management strategies in resource-limited settings remains limited. This observational study in adolescents with confirmed bleeding disorders with HMB at a tertiary hemophilia treatment centre evaluated menstrual blood loss and QOL after a standard regimen of progesterone, tranexamic acid and iron; blood products or clotting factor concentrates were reserved for refractory bleeding. Twenty adolescents were included (2020-2025); von Willebrand disease (n = 11), chronic immune thrombocytopenia (n = 4), congenital aplastic anemia (n = 3), afibrinogenemia (n = 1), and factor VII deficiency (n = 1). Median PBAC score at presentation was 300 (range 190-500). Eighteen patients (90%) had anemia and prior transfusion exposure. After therapy, median PBAC declined to 100 (range 60-150). Hemoglobin improved steadily and no patient required further red cell transfusion during a median follow-up of four years. Hemostatic products were required only in two patients while on this regimen. Quality-of-life scores improved across physical, emotional, and social domains. A low-cost regimen combining progesterone, antifibrinolytic therapy, and iron effectively controls HMB, corrects anemia, reduces transfusion and factor utilization, and improves QOL in adolescents with bleeding disorders in resource-constrained settings.
2020-01-22 | Fibrinogen Columbus II: A novel c.1075G>T mutation in the FGG gene causing hypodysfibrinogenemia and thrombosis in an adolescent male.
Hypodysfibrinogenemia, the least frequently reported congenital fibrinogen disorder is characterized by low circulating levels of a dysfunctional protein, and is associated with phenotypic features of both hypo- and dysfibrinogenemia. Herein, we report an adolescent male with unprovoked venous thromboembolism and hypodysfibrinogenemia. Patient had recurrent, progressive thrombosis despite therapeutic anticoagulation with both low molecular weight heparin and warfarin. He had clinical and radiological improvement after transition to a direct thrombin inhibitor. Sequencing of the FGG gene identified a novel heterozygous mutation, c.1075G>T. Structural visualization of the identified variant was pursued and suggested that the mutation likely destabilizes the Ca2+ -binding site of fibrinogen resulting in pathogenicity.
2015-08-04 | Thrombosis of abdominal aorta in congenital afibrinogenemia: case report and review of literature.
Thrombotic events in congenital hypo-afibrinogenemia have been rarely reported, either in association or not with replacement therapy or thrombotic risk factors. We describe clinical findings and management of thrombosis of abdominal aorta with peripheral embolism in a patient with congenital afibrinogenemia. A review of arterial thrombosis in inherited hypo-afibrinogenemia was also performed. The patient with a severe bleeding history requiring prophylaxis with fibrinogen concentrates (FC) was admitted for ischaemia of the 4th right toe. An angio-CT of abdominal aorta showed a thrombosis from the origin of renal arteries to the carrefour with a distal floating part. No thrombotic risk factors were found; a previous traumatic lesion of aortic wall might have triggered the thrombus formation, whereas the role of FC prophylaxis remains uncertain. The patient was successfully treated with FC, enoxaparin followed by fondaparinux, and low-dose aspirin without bleeding or thrombosis recurrence. After 2 years, aortic thrombus was almost completely recovered. Sixteen hypo/afibrinogenemia patients with arterial thrombosis were found in Literature, showing that thrombosis often occurs at a young age, involves large vessels, its recurrence is not unusual, and therapeutic strategy is not defined yet. Our therapeutic approach was effective and also safe, but further studies are needed to improve the knowledge of pathogenesis and the anti-thrombotic management in this peculiar setting.
2015-03-30 | Coexistence of hypofibrinogenemia and factor V Leiden mutation: is the balance shifted to thrombosis?
Congenital hypofibrinogenemia and afibrinogenemia are usually associated with an increased risk of bleeding, but occurrence of arterial or venous thrombosis has also been reported in individuals with fibrinogen deficiency. This study reports on a 25-year-old patient with hypofibrinogenemia (fibrinogen 0.6 g/l) and congenital thrombophilia due to heterozygous factor V Leiden mutation who developed spontaneous deep-vein thrombosis (DVT) in the right lower extremity. Regardless of hypofibrinogenemia, he was receiving anticoagulant therapy over 6 months, with no occurrence of bleeding. His father is also a heterozygous carrier of factor V Leiden, but with normal fibrinogen level and he remained asymptomatic despite having experienced surgery in the past. This case, as well as data from literature, suggests that risk of thrombosis in carriers of factor V Leiden mutation is not counterbalanced by moderate congenital hypofibrinogenemia, and that antithrombotic prophylaxis should not be omitted in high-risk situations for occurrence of thrombosis in patients with coinheritance of hypofibrinogenemia and factor V Leiden mutation.
2012-08-14 | Thrombosis in rare bleeding disorders.
Inherited deficiencies of blood coagulation factors are usually associated with lifelong bleeding tendency. In addition to Haemophilias A and B and von Willebrand disease, congenital deficiencies of such factors as fibrinogen, prothrombin (FII)), FV, FVII, FX, FXI, FXIII, and combined deficiencies occur and can lead to a diversity of clinical conditions. Paradoxically, for some of these disorders associated with significant bleeding tendency there are reports of thrombotic events, both arterial and venous. Thrombosis in hemophilia patients has a multifactorial pathogenesis and the main conditions associated with this complication are the use of long-term central venous catheters, intensive replacement therapy usually in the setting of surgical procedures, the use of bypassing agents or the coexistence of acquired or inherited prothrombotic risk factors. Regarding other rare bleeding disorders, thrombotic phenomena has been described particularly in patients with afibrinogenemia, FXI and FVII deficiency and the events can occur even in young patients, in the presence of concomitant risk factors or spontaneously. Replacement therapy must be individualized and should take into account past history of haemostatic challenges, family history of bleeding and thrombosis, just like the level of factor. For mild deficiencies when patients are asymptomatic the use of antithrombotic prophylaxis must be considered with or without concomitant use of replacement therapy. In patients with history of thrombosis it may be helpful to perform a thrombophilia screening to exclude coexisting prothrombotic defects and for all patients it is recommended to control known cardiovascular disease risk factors.
other
2026-03-06 | The fibrinogen αC region promotes arterial thrombosis in the context of hypofibrinogenemia.
Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19 of 264 (∼7%) patients developed arterial thrombosis, including 4 of 41 (∼10%) patients with hypofibrinogenemia. However, 0 of 8 patients with fibrinogen αC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen αC region on arterial thrombosis, 2 mouse models were employed: (1) wild-type mice treated with lipid nanoparticles encapsulating small interfering RNA against fibrinogen (siFga) and (2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated αC region. Although siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the αC region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of αC-region-platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wild-type mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ1 administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen αC region promotes arterial thrombosis in hypofibrinogenemic conditions.
2026-02-05 | Fibrin-bound thrombin determines clot structure and blood thrombogenicity in normofibrinogenemia and dysfibrinogenemia.
In thrombosis and hemostasis, coagulation and platelet activation pathways culminate to form solid fibrin clots, which can become vaso-occlusive or prevent excessive bleeding. We report a novel mechanism describing how developing fibrin clots prolong and modulate the reactivity of thrombin, an enzyme propagating platelet and coagulation activation and forming fibrin from fibrinogen. Using immunological and genetic approaches, we delineate how thrombin bound to the Aa and Bb chains of fibrin E-domains regulates lateral fibrin fiber extension. Our data reveal that fibrin-bound thrombin remains active and is temporarily protected against inactivation by antithrombin-III. Immunological displacement of thrombin from fibrin profoundly lowered its capacity, whereas a peptide mimicking the Aa-chain binding-site increased its reactivity. In a cohort of patients with congenital dysfibrinogenemia, carrying FGA, FGB or FGG mutations associated with bleeding or thrombosis phenotypes, we noticed a high thrombin capacity and suppressed thrombin-antithrombin-III complex formation, pointing to a prolonged active thrombin lifetime, likely due to abnormal formation of thrombin-containing fibrin. In conclusion, the combination of impaired clotting and increased thrombogenicity may explain the paradoxical bleeding and thrombotic complications observed in such patients. Development of fibrin-directed agents may offer new therapeutic opportunities to normalize hemostasis or prevent thrombosis.
2023-08-29 | Antibodies against Noncatalytic B Subunit of Factor XIII Inhibit Activation of Factor XIII and Fibrin Crosslinking.
Coagulation factor XIII (FXIII) is a proenzyme of plasma transglutaminase. It comprises two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). We previously reported that alloantibodies against FXIII-B could promote FXIII clearance in a patient with congenital FXIII-B deficiency who had received infusions of plasma-derived human FXIII (A2B2 heterotetramer). We aimed to investigate whether anti-FXIII-B antibodies affect the catalytic function of FXIII. FXIII activation and fibrin crosslinking were examined in the presence of patient plasma, isolated patient IgG, or rat anti-FXIII-B monoclonal antibodies. Alloantibody levels were increased by repeated infusions of plasma-derived A2B2 heterotetramer, which enhanced binding to the functionally important FXIII-B sushi domains. The patient plasma strongly inhibited cleavage of the FXIII-A activation peptide, amine incorporation, and fibrin crosslinking in normal plasma. Furthermore, anti-FXIII-B alloantibodies blocked the formation of the complex of FXIII-B with FXIII-A, and fibrinogen. Rat monoclonal antibodies against the 10th sushi domain of FXIII-B inhibited the incorporation of FXIII-B to fibrin, FXIII activation (i.e., cleavage of FXIII-A activation peptide), and ultimately fibrin crosslinking in normal plasma, independent of their effect on heterotetramer assembly with FXIII-A. Alloantibody binding to the A2B2 heterotetramer blocked the access of thrombin to the FXIII-A cleavage site, as indicated by the reaction of the alloantibodies to the A2B2 heterotetramer and FXIII-B, but not to FXIII-A. Anti-FXIII-B antibodies binding to the A2B2 heterotetramer and FXIII-B inhibited FXIII activation and its crosslinking function despite being directed against its noncatalytic subunit (FXIII-B).
proteins
2026-08-27 | Fibrinogen Concentrate in Acute Hemorrhage: Mechanistic Insight, Thresholds, and Targeted Replacement.
Fibrinogen is an essential component of hemostasis and clot formation that stabilizes the platelet-dependent primary hemostatic process. Low fibrinogen levels can be primary (congenital) or secondary (acquired). Acquired hypofibrinogenemia may result from chronic diseases (e.g., liver, autoimmune diseases, and malignancies) or major hemorrhage (e.g., trauma, surgery). Low fibrinogen levels are both a symptom and a precipitating factor for coagulopathy and ongoing bleeding. Fibrinogen repletion with fibrinogen-containing products is important for managing coagulopathic bleeding with suspected or documented hypofibrinogenemia. Different available fibrinogen sources include fibrinogen concentrate, cryoprecipitate, and frozen plasma and vary based on multiple factors including fibrinogen content, purity, other clotting or non-clotting proteins (e.g., immunomodulating proteins or proteins of unknown function), preparation time, safety, volumes, and availability. Fibrinogen replacement strategies have been studied in trauma but also in patients undergoing spine, cytoreductive, and cardiac surgery. In this review, we discuss the physiological actions of fibrinogen, strategies for control of coagulopathic bleeding related to hypofibrinogenemia, and the therapeutic, logistical, and economic factors that influence treatment decisions. In addition, current guidelines and clinical studies were considered regarding the formation of evidence-based treatment strategies that can be individualized at the patient's bedside.
2026-07-14 | Perianal Crohn Disease in a Patient With Congenital Afibrinogenemia: A Multidisciplinary Therapeutic Management Challenge.
Congenital afibrinogenemia is a rare autosomal recessive coagulation disorder characterized by absent or severely reduced circulating fibrinogen levels, leading to variable hemorrhagic manifestations. The coexistence of congenital afibrinogenemia and Crohn disease is exceptionally rare and represents a major diagnostic and therapeutic challenge, particularly in patients with active fistulizing perianal disease requiring repeated invasive procedures and immunosuppressive therapy. A 20-year-old woman with congenital afibrinogenemia diagnosed during childhood presented with chronic bloody diarrhea and perianal symptoms. Her bleeding history included umbilical cord bleeding, post-vaccination bleeding, recurrent ecchymoses, and fibrinogen levels below 0.4 IU/L. Seven months before admission, she developed a perianal abscess requiring surgical drainage, followed by persistent mucous and bloody diarrhea. Imaging demonstrated inflammatory rectal thickening and an active horseshoe anal fistula. Because of the anticipated hemorrhagic risk associated with endoscopic biopsies, intravenous fibrinogen concentrate was administered before endoscopy. The diagnosis of colonic Crohn disease with active fistulizing perianal involvement was established based on clinical, radiological, endoscopic, and histopathological findings. Following multidisciplinary evaluation, treatment with infliximab and azathioprine was initiated. During follow-up, recurrent epistaxis was successfully controlled with fibrinogen replacement therapy, while gastrointestinal and perianal symptoms markedly improved without major hemorrhagic, thrombotic, or infectious complications. This association of congenital afibrinogenemia with active fistulizing perianal Crohn disease highlights the complexity of balancing inflammatory control, procedural safety, and hemorrhagic risk. Individualized multidisciplinary management and appropriate peri-procedural hemostatic support are essential to optimize outcomes in this exceptionally rare clinical setting.
2026-06-24 | Comparative Biochemical and Functional Characterization of a Novel Human Fibrinogen Concentrate (BT524) and Established Plasma-Derived Fibrinogen Concentrates
Abstract Human fibrinogen concentrate is used as replacement therapy for congenital and acquired fibrinogen deficiencies. Despite similar manufacturing principles, compositional differences among products may affect clot quality and hemostatic efficacy. BT524 (Biotest) is a newly developed human fibrinogen concentrate with proven clinical safety and efficacy. The objective of this study was to compare the biochemical composition and in vitro functional characteristics of BT524 with those of two commercially available plasma-derived fibrinogen concentrates (Products I and II). Three independent batches of each human fibrinogen concentrate were analyzed for the total and clottable protein, fibrinogen antigen, fibrinogen activity by Clauss, clotting factors, degradation markers (fibrinopeptide A and D-dimer), sub-visible particles, and aggregates. Maximum clot firmness and dynamics were assessed using rotational thromboelastometry (fibrin-based thromboelastometry). Fibrinogen deficient plasma with low factor XIII content was spiked each fibrinogen concentrate and increasing concentrations of factor XIII (0–0.8 U/mL). BT524 showed consistent fibrinogen content but contained no active factor VIII, factor XIII, or von Willebrand factor, indicating a precisely defined composition. Levels of degradation markers, aggregates, and sub-visible particles were markedly lower than in comparator products, reflecting the superior biochemical purity of BT524. BT524 achieved significantly higher maximum clot firmness than Product I (p<0.0001) and demonstrated comparable performance with Product II. Spiking of factor XIII resulted in an additional increase in maximum clot firmness in BT524 and Product II, but not in Product I, proving functional factor XIII susceptibility of BT524. BT524 demonstrates high biochemical purity and robust functional clot formation. These findings highlight that fibrinogen concentrates differ in composition, functionality and molecular integrity, which determines clot quality and hemostatic performance.
2026-06-04 | Quantitative fibrinogen disorders: A retrospective study from a tertiary care centre in India.
Background and objectives Congenital fibrinogen disorders encompass both quantitative and qualitative abnormalities of fibrinogen, characterised by variable bleeding or thrombotic tendencies. Due to their rarity and varied presentations, delays in diagnosis are common, which can significantly impact patient outcomes. This study was conducted to describe the clinical and demographic profiles of patients with congenital quantitative fibrinogen disorders over a 20-year period (2003-2024) at a tertiary care centre. Methods A retrospective analysis was conducted using laboratory records to identify 17 patients with quantitative fibrinogen disorders, characterised by prolonged prothrombin time (PT), activated partial thromboplastin time (APTT), and undetectable or low fibrinogen levels. Only 10 out of 17 patients could be contacted for follow up. The clinical presentation, including scoring of bleeding symptoms using the International Society on Thrombosis and Haemostasis - Bleeding Assessment Tool (ISTH-BAT), as well as demographic variables such as age of onset, first visit to our hospital, and diagnostic delays, were recorded. Treatment and follow up data were recorded. Results Majority of patients showed symptoms in the neonatal period, with umbilical bleeding as the most common initial manifestation, followed by post-traumatic and cutaneous bleeding. Despite early symptom onset, a median diagnostic delay of four years was observed. Seven cases were under regular follow up with on-demand therapy. Three patients died during follow up. Most of the cases received fresh frozen plasma. Interpretation and conclusions This study describes the clinical profile of quantitative fibrinogen disorders and emphasises the importance of increased awareness, early diagnosis, and standardised management in these patients. Given the significant risk of bleeding, proactive measures such as patient education and close monitoring are crucial.
2026-04-28 | The use of fibrinogen concentrate in coagulation testing aids in the diagnosis and management of rare bleeding disorders.
Many clinical laboratories lack the methods or resources to quickly identify rare haemorrhagic diseases, such as genetic/acquired fibrinogen defects and factor XIII deficiency. This report explored the value of human fibrinogen concentrate in the diagnosis and management of rare bleeding disorders through three case studies. Case 1 involved acquired hypofibrinogenemia caused by snake bite, where the coagulation abnormality was corrected by adding fibrinogen in vitro, confirming the mechanism of snake venom-specific degradation of fibrinogen. Case 2 utilised fibrinogen solution to establish a thromboelastography mixing test for rapid diagnosis of autoimmune factor XIII inhibitors. Case 3 improved platelet aggregation function in patients with congenital abnormal fibrinogenaemia through fibrinogen solution. These case studies showed that fibrinogen concentrate may serve as a specific additive to assist in the rapid identification of coagulation dysfunction and guide precise treatment.
cell therapies
2024-07-03 | Budd-Chiari syndrome associated with congenital afibrinogenaemia reversed after orthotopic liver transplant.
A woman in her mid-20s, a known case of congenital afibrinogenaemia, presented with abdominal pain and distension. She was diagnosed with decompensated liver cirrhosis due to Budd-Chiari syndrome. She underwent deceased donor liver transplantation. Preoperatively, her serum fibrinogen level was undetectable and prothrombin time and international normalised ratio (INR) were unrecordable. Intraoperatively, she was given thromboelastography-guided human fibrinogen concentrate. Postoperatively, her fibrinogen, prothrombin time and INR normalised rapidly. This report summarises the rare occurrence of a complication of hypercoagulability (Budd-Chiari syndrome) in the setting of congenital hypocoagulability (congenital afibrinogenaemia). In this report, we discuss the simultaneous management of these two clinical problems and the curative role of liver transplantation.
2021-05-14 | Liver transplantation as a novel strategy for resolution of congenital afibrinogenemia in a pediatric patient.
Fibrinogen replacement therapy is a treatment mainstay for patients with afibrinogenemia and significant bleeding. A male infant with congenital afibrinogenemia and several spontaneous hemarthroses commenced cryoprecipitate prophylaxis but developed severe urticarial reactions. He transitioned to a human fibrinogen concentrate (HFC) (RiaSTAP® , CSL Behring; 70 mg/kg biweekly) but continued experiencing hemarthroses (estimated annualized bleeding rate [ABR]: 5-6) and severe anaphylactic reactions, despite pre- and postinfusion medications. Following switching to a new HFC (Fibryga® , Octapharma; 50 mg/kg biweekly), ABR was 0-1 with no further infusion reactions. Aged 9 years, because of limited quality of life, development of obesity and fatty liver disease, he underwent orthotopic liver transplant (OLT) under HFC coverage. Pharmacokinetic analysis guided presurgical fibrinogen levels > 150 mg/dL. No intraoperative HFC infusions were required. Coagulation profile and fibrinogen levels remained within normal limits during and posttransplant. To our knowledge, this is the first pediatric report of afibrinogenemia successfully treated with OLT.
2011-06-28 | Recurrent massive hemoperitoneum due to ovulation as a clinical sign in congenital afibrinogenemia.
Massive hemoperitoneum due to ovulation is a rare but serious and life-threatening complication for women with coagulation disorders, and may lead to surgical interventions and even oophorectomy. Congenital afibrinogenemia is an uncommon coagulation disorder usually discovered during childhood. Intraabdominal bleeding due to ovulation is very rare in these patients and only a few cases of corpus luteum rupture and hemoperitoneum in afibrinogenemic patients have been described. In all women, the diagnosis was known since childhood. We report on a 24-year-old woman with congenital afibrinogenemia with recurrent massive intraabdominal bleeding due to ovulation as the presenting clinical sign. Exploratory laparotomy and excision of the ruptured follicle was performed at the first bleeding episode; the second episode was managed with fresh frozen plasma and blood transfusions. Conservative management is crucial for these patients. If surgery cannot be avoided, a conservative surgical approach should be chosen to preserve ovarian function.
2008-04-01 | Manipulating the quality control pathway in transfected cells: low temperature allows rescue of secretion-defective fibrinogen mutants.
Congenital afibrinogenemia is characterized by the absence of fibrinogen, a hexamer composed of two copies of three polypeptides, Aalpha. Bbeta and gamma. The disease is caused by mutations in one of the three fibrinogen-encoding genes, FGA, FGB and FGG. Among these, several mutations have been reported to specifically impair fibrinogen secretion. We previously showed that secretion-defective fibrinogen mutants are retained in a pre-Golgi compartment and demonstrated the importance of the homologous betaC and gammaC domains in secretion. Here our aim was to restore the secretion of these mutants and study the properties of the rescued mutant molecules. COS-7 cells were transfected and incubated with chemical chaperones or at low temperature. Clotting assays and plasmin digestion studies were performed to characterize secreted fibrinogen molecules. The secretion defect of two missense mutants but not that of late-truncating mutants could be partially corrected by incubating cells at 27 degrees C. By contrast, exposure of cells to chemical chaperones i.e. 4-phenylbutyrate, dimethyl sulfoxide or trimethylamine N-oxide had no effect. The mutants rescued at 27 degrees C were incorporated into fibrin clots and formed factor XIII-mediated gamma-gamma dimers in contrast to the dysfibrinogenemia Vlissingen/Frankfurt IV mutant, a negative control for these assays. However, plasmin digestion analyses revealed aberrant patterns for the mutants compared to normal fibrinogen. Low temperature can restore the secretion of a subset of mutant fibrinogen molecules demonstrating that therapeutic manipulation of the quality control pathway is feasible for afibrinogenemia even though functional assays suggested a non-native conformation for the mutant molecules analyzed.
1985-09-06 | Congenital afibrinogenemia and recurrent early abortion: a case report.
The role of the fibrinogen molecule in the maintenance of normal pregnancy is not yet well understood; however, several cases have been previously reported in which failure to complete normal pregnancy was associated with either hypofibrinogenemia, dysfibrinogenemia, or deficiency in factor XIII (fibrin-stabilizing factor) which is important for the crosslinking of the fibrin. A case of congenital afibrinogenemia is described. The patient, a 22-yr-old woman, who suffered from a moderate hemorrhagic tendency associated with very low (less than 10 mg/dl) plasma fibrinogen levels, had three consecutive spontaneous abortions. In view of the previous cases reported, the question is raised whether patients with low or abnormal fibrinogen should be treated with plasma transfusions in order to maintain a normal pregnancy.
gene therapies
2022-02-01 | An FGA Frameshift Variant Associated with Afibrinogenemia in Dachshunds.
Congenital fibrinogen disorders are very rare in dogs. Cases of afibrinogenemia have been reported in Bernese Mountain, Bichon Frise, Cocker Spaniel, Collie, Lhasa Apso, Viszla, and St. Bernard dogs. In the present study, we examined four miniature wire-haired Dachshunds with afibrinogenemia and ascertained their pedigree. Homozygosity mapping and a genome-wide association study identified a candidate genomic region at 50,188,932-64,187,680 bp on CFA15 harboring FGB (fibrinogen beta chain), FGA (fibrinogen alpha chain), and FGG (fibrinogen gamma-B chain). Sanger sequencing of all three fibrinogen genes in two cases and validation of the FGA-associated mutation (FGA:g.6296delT, NC_006597.3:g.52240694delA, rs1152388481) in pedigree members showed a perfect co-segregation with afibrinogenemia-affected phenotypes, obligate carriers, and healthy animals. In addition, the rs1152388481 variant was validated in 393 Dachshunds and samples from 33 other dog breeds. The rs1152388481 variant is predicted to modify the protein sequence of both FGA transcripts (FGA201:p.Ile486Met and FGA-202:p.Ile555Met) leading to proteins truncated by 306 amino acids. The present data provide evidence for a novel FGA truncating frameshift mutation that is very likely to explain the cases of severe bleeding due to afibrinogenemia in a Dachshund family. This mutation has already been spread in Dachshunds through carriers before cases were ascertained. Genetic testing allows selective breeding to prevent afibrinogenemia-affected puppies in the future.
2015-10-15 | In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes.
Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bβ and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGA homozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality. To explore a targeted gene therapy approach for patients with congenital afibrinogenemia. At the time of transplant, the patient's FGA-deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα-chain. FGA-transduced hepatocytes produced fully functional fibrinogen in vitro. Orthotopic liver transplantation is a possible rescue treatment for failure of on-demand fibrinogen replacement therapy. In addition, we provide evidence that hepatocytes homozygous for a large FGA deletion can be genetically modified to restore Aα-chain protein expression and secrete a functional fibrinogen hexamer.
2001-08-02 | Fibrinogen gene mutations accounting for congenital afibrinogenemia.
This article reviews recent progress made in understanding the molecular basis of congenital afibrinogenemia, an autosomal recessive coagulation disorder characterized by the complete absence of detectable fibrinogen. We have identified the first causative mutations for this disorder in a non-consanguineous Swiss family; these were homozygous deletions of approximately 11 kb of the fibrinogen alpha chain (FGA) gene. Haplotype data implied that the deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. All the deletions were identical to the base pair, and probably resulted from non-homologous (illegitimate) recombination. In a subsequent study of 13 unrelated patients with congenital afibrinogenemia we analyzed the FGA gene in order to identify the causative mutations, and to determine the prevalence of the 11-kb FGA deletion. Although this deletion was found in an additional unrelated patient, the most common mutation was at the donor splice site of FGA intron 4 (IVS4 + 1 G > T). Three frameshift mutations, two nonsense mutations, and one other splice site mutation were also characterized. Other studies identified one further FGA nonsense mutation, two FGB missense mutations, and one FGG nonsense mutation, all in homozygosity in a single patient. In conclusion, the majority of patients have truncating mutations in the FGA gene although, intuitively, all three fibrinogen genes could be predicted to be equally implicated. These results will facilitate molecular diagnosis of the disorder, permit prenatal diagnosis for families who so desire, and pave the way for new therapeutic approaches such as gene therapy.
small molecules
2026-03-22 | Managing heavy menstrual bleeding in adolescents with bleeding disorders: Outcomes from a pragmatic LMIC approach.
Heavy menstrual bleeding (HMB) a common manifestation of bleeding disorders in adolescents contributes to anemia, transfusions, and impaired quality-of-life (QOL). Evidence supporting practical management strategies in resource-limited settings remains limited. This observational study in adolescents with confirmed bleeding disorders with HMB at a tertiary hemophilia treatment centre evaluated menstrual blood loss and QOL after a standard regimen of progesterone, tranexamic acid and iron; blood products or clotting factor concentrates were reserved for refractory bleeding. Twenty adolescents were included (2020-2025); von Willebrand disease (n = 11), chronic immune thrombocytopenia (n = 4), congenital aplastic anemia (n = 3), afibrinogenemia (n = 1), and factor VII deficiency (n = 1). Median PBAC score at presentation was 300 (range 190-500). Eighteen patients (90%) had anemia and prior transfusion exposure. After therapy, median PBAC declined to 100 (range 60-150). Hemoglobin improved steadily and no patient required further red cell transfusion during a median follow-up of four years. Hemostatic products were required only in two patients while on this regimen. Quality-of-life scores improved across physical, emotional, and social domains. A low-cost regimen combining progesterone, antifibrinolytic therapy, and iron effectively controls HMB, corrects anemia, reduces transfusion and factor utilization, and improves QOL in adolescents with bleeding disorders in resource-constrained settings.
2020-01-22 | Fibrinogen Columbus II: A novel c.1075G>T mutation in the FGG gene causing hypodysfibrinogenemia and thrombosis in an adolescent male.
Hypodysfibrinogenemia, the least frequently reported congenital fibrinogen disorder is characterized by low circulating levels of a dysfunctional protein, and is associated with phenotypic features of both hypo- and dysfibrinogenemia. Herein, we report an adolescent male with unprovoked venous thromboembolism and hypodysfibrinogenemia. Patient had recurrent, progressive thrombosis despite therapeutic anticoagulation with both low molecular weight heparin and warfarin. He had clinical and radiological improvement after transition to a direct thrombin inhibitor. Sequencing of the FGG gene identified a novel heterozygous mutation, c.1075G>T. Structural visualization of the identified variant was pursued and suggested that the mutation likely destabilizes the Ca2+ -binding site of fibrinogen resulting in pathogenicity.
2015-08-04 | Thrombosis of abdominal aorta in congenital afibrinogenemia: case report and review of literature.
Thrombotic events in congenital hypo-afibrinogenemia have been rarely reported, either in association or not with replacement therapy or thrombotic risk factors. We describe clinical findings and management of thrombosis of abdominal aorta with peripheral embolism in a patient with congenital afibrinogenemia. A review of arterial thrombosis in inherited hypo-afibrinogenemia was also performed. The patient with a severe bleeding history requiring prophylaxis with fibrinogen concentrates (FC) was admitted for ischaemia of the 4th right toe. An angio-CT of abdominal aorta showed a thrombosis from the origin of renal arteries to the carrefour with a distal floating part. No thrombotic risk factors were found; a previous traumatic lesion of aortic wall might have triggered the thrombus formation, whereas the role of FC prophylaxis remains uncertain. The patient was successfully treated with FC, enoxaparin followed by fondaparinux, and low-dose aspirin without bleeding or thrombosis recurrence. After 2 years, aortic thrombus was almost completely recovered. Sixteen hypo/afibrinogenemia patients with arterial thrombosis were found in Literature, showing that thrombosis often occurs at a young age, involves large vessels, its recurrence is not unusual, and therapeutic strategy is not defined yet. Our therapeutic approach was effective and also safe, but further studies are needed to improve the knowledge of pathogenesis and the anti-thrombotic management in this peculiar setting.
2015-03-30 | Coexistence of hypofibrinogenemia and factor V Leiden mutation: is the balance shifted to thrombosis?
Congenital hypofibrinogenemia and afibrinogenemia are usually associated with an increased risk of bleeding, but occurrence of arterial or venous thrombosis has also been reported in individuals with fibrinogen deficiency. This study reports on a 25-year-old patient with hypofibrinogenemia (fibrinogen 0.6 g/l) and congenital thrombophilia due to heterozygous factor V Leiden mutation who developed spontaneous deep-vein thrombosis (DVT) in the right lower extremity. Regardless of hypofibrinogenemia, he was receiving anticoagulant therapy over 6 months, with no occurrence of bleeding. His father is also a heterozygous carrier of factor V Leiden, but with normal fibrinogen level and he remained asymptomatic despite having experienced surgery in the past. This case, as well as data from literature, suggests that risk of thrombosis in carriers of factor V Leiden mutation is not counterbalanced by moderate congenital hypofibrinogenemia, and that antithrombotic prophylaxis should not be omitted in high-risk situations for occurrence of thrombosis in patients with coinheritance of hypofibrinogenemia and factor V Leiden mutation.
2012-08-14 | Thrombosis in rare bleeding disorders.
Inherited deficiencies of blood coagulation factors are usually associated with lifelong bleeding tendency. In addition to Haemophilias A and B and von Willebrand disease, congenital deficiencies of such factors as fibrinogen, prothrombin (FII)), FV, FVII, FX, FXI, FXIII, and combined deficiencies occur and can lead to a diversity of clinical conditions. Paradoxically, for some of these disorders associated with significant bleeding tendency there are reports of thrombotic events, both arterial and venous. Thrombosis in hemophilia patients has a multifactorial pathogenesis and the main conditions associated with this complication are the use of long-term central venous catheters, intensive replacement therapy usually in the setting of surgical procedures, the use of bypassing agents or the coexistence of acquired or inherited prothrombotic risk factors. Regarding other rare bleeding disorders, thrombotic phenomena has been described particularly in patients with afibrinogenemia, FXI and FVII deficiency and the events can occur even in young patients, in the presence of concomitant risk factors or spontaneously. Replacement therapy must be individualized and should take into account past history of haemostatic challenges, family history of bleeding and thrombosis, just like the level of factor. For mild deficiencies when patients are asymptomatic the use of antithrombotic prophylaxis must be considered with or without concomitant use of replacement therapy. In patients with history of thrombosis it may be helpful to perform a thrombophilia screening to exclude coexisting prothrombotic defects and for all patients it is recommended to control known cardiovascular disease risk factors.
other
2026-03-06 | The fibrinogen αC region promotes arterial thrombosis in the context of hypofibrinogenemia.
Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19 of 264 (∼7%) patients developed arterial thrombosis, including 4 of 41 (∼10%) patients with hypofibrinogenemia. However, 0 of 8 patients with fibrinogen αC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen αC region on arterial thrombosis, 2 mouse models were employed: (1) wild-type mice treated with lipid nanoparticles encapsulating small interfering RNA against fibrinogen (siFga) and (2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated αC region. Although siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the αC region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of αC-region-platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wild-type mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ1 administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen αC region promotes arterial thrombosis in hypofibrinogenemic conditions.
2026-02-05 | Fibrin-bound thrombin determines clot structure and blood thrombogenicity in normofibrinogenemia and dysfibrinogenemia.
In thrombosis and hemostasis, coagulation and platelet activation pathways culminate to form solid fibrin clots, which can become vaso-occlusive or prevent excessive bleeding. We report a novel mechanism describing how developing fibrin clots prolong and modulate the reactivity of thrombin, an enzyme propagating platelet and coagulation activation and forming fibrin from fibrinogen. Using immunological and genetic approaches, we delineate how thrombin bound to the Aa and Bb chains of fibrin E-domains regulates lateral fibrin fiber extension. Our data reveal that fibrin-bound thrombin remains active and is temporarily protected against inactivation by antithrombin-III. Immunological displacement of thrombin from fibrin profoundly lowered its capacity, whereas a peptide mimicking the Aa-chain binding-site increased its reactivity. In a cohort of patients with congenital dysfibrinogenemia, carrying FGA, FGB or FGG mutations associated with bleeding or thrombosis phenotypes, we noticed a high thrombin capacity and suppressed thrombin-antithrombin-III complex formation, pointing to a prolonged active thrombin lifetime, likely due to abnormal formation of thrombin-containing fibrin. In conclusion, the combination of impaired clotting and increased thrombogenicity may explain the paradoxical bleeding and thrombotic complications observed in such patients. Development of fibrin-directed agents may offer new therapeutic opportunities to normalize hemostasis or prevent thrombosis.
2023-08-29 | Antibodies against Noncatalytic B Subunit of Factor XIII Inhibit Activation of Factor XIII and Fibrin Crosslinking.
Coagulation factor XIII (FXIII) is a proenzyme of plasma transglutaminase. It comprises two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). We previously reported that alloantibodies against FXIII-B could promote FXIII clearance in a patient with congenital FXIII-B deficiency who had received infusions of plasma-derived human FXIII (A2B2 heterotetramer). We aimed to investigate whether anti-FXIII-B antibodies affect the catalytic function of FXIII. FXIII activation and fibrin crosslinking were examined in the presence of patient plasma, isolated patient IgG, or rat anti-FXIII-B monoclonal antibodies. Alloantibody levels were increased by repeated infusions of plasma-derived A2B2 heterotetramer, which enhanced binding to the functionally important FXIII-B sushi domains. The patient plasma strongly inhibited cleavage of the FXIII-A activation peptide, amine incorporation, and fibrin crosslinking in normal plasma. Furthermore, anti-FXIII-B alloantibodies blocked the formation of the complex of FXIII-B with FXIII-A, and fibrinogen. Rat monoclonal antibodies against the 10th sushi domain of FXIII-B inhibited the incorporation of FXIII-B to fibrin, FXIII activation (i.e., cleavage of FXIII-A activation peptide), and ultimately fibrin crosslinking in normal plasma, independent of their effect on heterotetramer assembly with FXIII-A. Alloantibody binding to the A2B2 heterotetramer blocked the access of thrombin to the FXIII-A cleavage site, as indicated by the reaction of the alloantibodies to the A2B2 heterotetramer and FXIII-B, but not to FXIII-A. Anti-FXIII-B antibodies binding to the A2B2 heterotetramer and FXIII-B inhibited FXIII activation and its crosslinking function despite being directed against its noncatalytic subunit (FXIII-B).
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Drug Discovery Landscape
3 orphan drug designations for Congenital fibrinogen deficiency, including 1 approved therapy.
3 orphan drug designations for Congenital fibrinogen deficiency, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
human fibrinogen concentrate, pasteurized [RiaSTAP] | proteins | FDA | Approved | CSL Behring, LLC |
recombinant human fibrinogen | proteins | FDA | — | Pharming Technologies B.V. |
Fibrinogen (human) | proteins | FDA | Alpha Therapeutic Corporation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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