Afibrinogenemia Research Articles

Clinical phenotypes and genotypes of congenital fibrinogen disorder: an analysis of 16 children

To investigate the clinical phenotypes and genotypes of children with congenital fibrinogen disorder (CFD). A retrospective analysis was conducted on the clinical data of 16 children with CFD. Polymerase chain reaction was used to amplify all exons and flanking sequences of the FGA, FGB, and FGG genes, and sequencing was performed to analyze mutation characteristics. Among the 16 children, there were 9 boys (56%) and 7 girls (44%), with a median age of 4 years at the time of attending the hospital. Among these children, 9 (56%) attended the hospital due to bleeding events, and 7 (44%) were diagnosed based on preoperative examination. The children with bleeding events had a significantly lower fibrinogen activity than those without bleeding events (P<0.05). Genetic testing was conducted on 12 children and revealed a total of 12 mutations, among which there were 4 novel mutations, i.e., c.80T>C and c.1368delC in the FGA gene and c.1007T>A and C.1053C>A in the FGG gene. There were 2 cases of congenital afibrinogenemia caused by null mutations of the FGA gene, with relatively severe bleeding symptoms. There were 7 cases of congenital dysfibrinogenemia mainly caused by heterozygous missense mutations of the FGG and FGA genes, and their clinical phenotypes ranged from asymptomatic phenotype to varying degrees of bleeding. The clinical phenotypes of children with CFD are heterogeneous, and the severity of bleeding is associated with the level of fibrinogen activity, but there is a weak association between clinical phenotype and genotype.

Post-Marketing Observational Study of the Safety and Efficacy of Fibrinogen Concentrate in Congenital Fibrinogen Deficiency in Patients of All Ages

Background and Significance: Congenital fibrinogen deficiency (CFD) is a rare coagulation disorder characterized by a lack or low levels of functional fibrinogen leading to inadequate clot formation. Patients with CFD may experience severe or frequent bleeding episodes (BEs), either spontaneously or following trauma or surgery. Human fibrinogen concentrate (HFC; Fibryga® [Octapharma]) can restore hemostasis, and its efficacy and safety has been demonstrated in interventional clinical studies of adult and pediatric patients. The primary objective of this planned observational study is to collect real-world evidence to further assess the safety profile of this HFC, in patients of all ages with congenital fibrinogen deficiency, by characterizing the risks of thrombosis and anaphylaxis following its administration for treatment of bleeding (Figure 1). The observational data collected in this study will provide a more comprehensive safety profile of this HFC in patients of all ages following its marketing authorization. Study Design and Methods: FORMA-07 (NCT03793426) is a prospective, non-interventional, multicenter, observational, post-marketing study. Patients of all ages with a documented diagnosis of CFD (i.e., congenital afibrinogenemia or hypofibrinogenemia) requiring on demand HFC for BE treatment are eligible for inclusion (Table 1). Exclusion criteria include other coagulation disorders, history of anti-fibrinogen inhibitors, and participation in concurrent clinical studies. This study will examine a highly purified, plasma derived, double virus inactivated/eliminated, lyophilized HFC, which will be used according to individual country approval and labelling, and individually dosed as per the locally approved package insert. Independent ethical committee approval will be sought prior to study start and freely given, written informed consent obtained from all participants, or legal guardians in the case of pediatric patients. This study will be conducted in accordance with the ethical principles laid down in the Declaration of Helsinki. The primary endpoint is the incidence of thromboembolic adverse drug reactions (ADRs) . Serious ADRs, ADRs of special interest (including thromboembolic events and anaphylaxis), and thromboembolic monitoring using the Wells Score will be documented. Hemostatic efficacy will be assessed as a secondary endpoint by the study investigator using a robust 4-point objective scale from 2 to 24 hours following treatment. FORMA-07 is ongoing and actively enrolling patients of all ages with CFD. The study aims to enroll ~25 patients over 7 years, collecting data from 105 BEs (≥10 major BEs in 10 patients). Results of HFC safety and efficacy will be continually monitored throughout the study. Completion is expected Q4 2027.

Prophylaxis and Treatment of Bleeding or Thrombosis with Fibrinogen Concentrate (Fibryga) in Patients with Congenital Hypofibrinogenemia or Dysfibrinogenemia

Congenital fibrinogen disorders (CFDs) are rare and make up approximately 0.6% of all inherited bleeding disorders. Two subtypes include a quantitative deficiency of fibrinogen, congenital afibrinogenemia (CA), congenital hypofibrinogenemia (CH), and qualitative defect of the fibrinogen molecule, congenital dysfibrinogenemia (CD). Patients with CD may have a thrombotic as well as a hemorrhagic disease phenotype. In the past, fresh frozen plasma or cryoprecipitate were the only options available for treatment and prevention of bleeding in patients with CFD. Today in the US, human plasma-derived concentrates (FIBRYGA, Octapharma, Lachlen, Switzerland, and RiaSTAP, CSL, Melbourne, Australia) are available and considered safe and effective treatment options for CD and CH. Guidelines for the treatment and prevention of bleeding is not established for CFDs, and especially for CD. We present eight clinical cases of patients with hypo- or dysfibrinogenemia that were effectively treated with a pooled, plasma-derived fibrinogen concentrate (FIBRYGA) either prophylactically for elective or urgent surgery, or post-traumatic injury. The mean age of patients treated was 34 years (min-max 8-70 years). Three patients were male and five, female. Four patients had CH and four, CD. FIBRYGA was used to prophylactically treat a total of ten surgical procedures and two post-traumatic events in these patients. Dosing of FIBRYGA was based on the goal peak plasma fibrinogen concentration and the manufacturer's prescribing information, but modified to align with local laboratory reference ranges for the functional fibrinogen test. No acute or delayed infusion reactions (nausea, fever, rigors, headache) and no hypersensitivity reactions were noted. One patient developed two adverse events, one thrombotic and one hemorrhagic. This patient underwent left, above the knee amputation (AKA) and had a complicated postoperative period due to her multiple comorbidities including type 2 diabetes, hypertension, and long standing, poorly-controlled, severe peripheral arterial disease. She presented nineteen days after receiving FIBRGYA with a PE and multiple DVTs. Fifty-nine days later she presented with wound dehiscence and underwent an extensive excisional debridement with postoperative bleeding deemed to be secondary to her strap sliding during surgery and acting as a tourniquet for venous blood flow. For the majority (86%) of our patients described here with CH and CD, FIBRYGA was well tolerated and effective in preventing post procedural or post traumatic bleeding complications. The post procedural bleeding noted in one patient may have been due to inadequate fibrinogen concentration or other comorbid conditions. Further clinical studies are needed to determine the role of FIBRGYA and other HFC in the treatment of patients with CFD, especially those with CD.

Congenital afibrinogenemia presenting with cellulitis in the lower back: A case report

Afibrinogenemia is a rare inherited bleeding disorder characterized by the complete absence of fibrinogen, a clotting protein essential for normal blood coagulation. We present a case of a 13-year-old girl diagnosed with afibrinogenemia at the age of 1 month, now admitted due to cellulitis in the lower back. Here, we have examined how to diagnose a case of these uncommon conditions and emphasized the management and treatment strategy for such a case.

Isolated Scalp Hematoma

Background: Congenital fibrinogen disorder is a rare autosomal recessive blood coagulation disorder, where majority of patients present with bleeding, whereas a few may paradoxically develop thrombosis. While many of the affected children have prolonged umbilical cord bleeding during the neonatal period, manifestations may go unnoticed till adolescence. We describe such a child with congenital afibrinogenemia Clinical Description: A 12-year-old boy presented with painless diffuse scalp swelling for 2 weeks without any antecedent history of trauma, hemarthrosis, muscle hematoma, or any skin bleed, except a history of prolonged bleeding post trauma since toddler age. Examination revealed diffuse, boggy, nonpulsatile swelling over the entire scalp, more prominent on the right side, without any focal neurological deficit. A noncontrast computed tomography head showed a scalp hematoma without any intracranial bleeding. Blood investigations revealed extremely elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT) with normal platelet counts and normal platelet morphology on peripheral smear. A detailed coagulation work-up revealed an extremely high thrombin time and an almost undetectable Factor I (fibrinogen) level. Genetic analysis revealed a homozygous single-base pair deletion in exon 5 of the fibrinogen gene of alpha chain, thus confirming the diagnosis of congenital afibrinogenemia. Management: The child was managed with multiple fresh frozen plasma transfusions and serial PT/aPTT monitoring. Once PT and aPTT were normalized, transfusions were discontinued. The child is currently on regular follow-up maintaining a fibrinogen level of more than 0.5 g/L. Genetic counseling was done for the family. Conclusion: Congenital afibrinogenemia may be detected late in adolescence with atypical bleeding manifestations. Awareness of this entity may help the physician to suspect this disease. Early and appropriate investigations can be conducted to identify the condition, so that appropriate management can be initiated.

Treatment of Congenital Afibrinogenemia in a Neonate With Critical Pulmonary Stenosis.

Fibrinogen deficiencies in neonates can lead to bleeding complications. In this report, we describe a case of congenital afibrinogenemia in a newborn with critical pulmonary stenosis who presented with bilateral cephalohematomas after an uncomplicated delivery. The initial use of cryoprecipitate was followed by administration of fibrinogen concentrate. We estimated a half-life of 24 to 48 hours with the concentrate product. This patient received fibrinogen replacement and had a subsequent successful cardiac repair. The drug's shorter half-life in this neonate contrasts with prior reports of longer half-life in older patients and is important to note in treating future neonatal patients with this diagnosis.

High incidence of intracranial haemorrhage in Egyptian children with congenital afibrinogenaemia.

Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality in patients with congenital afibrinogenaemia. Details on location of cerebral haemorrhage, management and neurological outcomes are lacking. We performed a retrospective study on Egyptian children with congenital afibrinogenaemia who experienced ICH, in order to estimate frequency, symptoms and neurological outcomes. Among 58 children with congenital afibrinogenaemia treated on demand, 18 (31%) had an history of ICH (28 episodes). The first ICH occurred at a median age of 1year (Q1-Q3 1-7 years). Impaired consciousness level, vomiting and seizures were the most common presenting symptoms. Spontaneous bleeding was associated with a more severe clinical presentation and worse neurological outcomes, including hydrocephaly and impaired cognitive development. Only half of ICH events (n=14) were treated in less than 24h from the onset of symptoms. Fibrinogen replacement by Fresh Frozen Plasma (FFP), cryoprecipitate or fibrinogen concentrates was administered in seven (25%), 19 (68%) and three (10%) ICH events, respectively. Overall, seven (25%) ICH occurring in four patients required a surgical intervention. After the ICH, six patients started secondary prophylaxis. The cumulative incidence of ICH at 10 years was 35% (95% CI 23-51) and at 20 years was 40% (95 CI% 26.7-58.8). In our cohort of children with congenital afibrinogenaemia, ICH was very frequent and associated with adverse neurological outcomes and death. Further studies are required to determine whether primary prophylaxis starting early in childhood is indicated after diagnosis.

Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia.

Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC). This post-hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a- and hypofibrinogenaemia. The analysis used data from the FORMA-01 (Phase 2), FORMA-02 and FORMA-04 (Phase 3) multinational, prospective, open-label studies in patients with a- and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA-01) and children (<12 years; FORMA-04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA-02 and FORMA-04 using an objective 4-point scale, with success defined as excellent/good. Median (range) age was 23 years for FORMA-01 (12-53; n=22), 26.5 years for FORMA-02 (12-54; n=25), and 6 years for FORMA-04 (1-10; n=13). Mean PK parameters were lower for children (AUC, Cmax , IVR; p=.02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41mg/kg (32.12-273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91mg/kg (47.45-262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis. As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable.

Kongenitalna afibrinogenemija kod novorođenčeta

Introduction: Congenital afibrinogenemia is a rare coagulation disorder characterized by a deficiency in the fibrinogen molecule. Fibrinogen is a hexameric glycoprotein consisting of a polypeptide chain encoded by FGB, FGA, and FGG and is required for normal hemostasis. Changes in FGA, FGB, and FGG may affect fibrinogen at different levels. As a result of these changes, fibrinogen cannot be detected in the blood. Clinical manifestations of such changes range from asymptomatic to life-threatening bleeding or thromboembolic events. Since it is an autosomal recessive disease, the risk is higher in children whose parents are related. Therefore, the disease is more common in regions where consanguineous marriage rates are high. Diagnosis is made by laboratory tests that show the absence of fibrinogen. These patients need to be treated with fibrinogen replacement therapy. Case presentation: This study reports the case of a newborn with congenital afibrinogenemia. The baby born from a first-degree consanguineous marriage was referred to our hospital due to bleeding and ecchymosis, and afibrinogenemia was diagnosed after coagulation tests were performed. Blood samples of the patient and his parents were sent to the Genetic Diseases Diagnosis Center for a genetic diagnosis of afibrinogenemia. A new homozygous mutation of FGB exon 7: c.1220c &gt; t (p.t407 m) (p.thr407 met) was identified in the patient. The patients' parents were heterozygous for the same mutation. Prophylaxis was not recommended for our patient who was asymptomatic in the follow-up. Conclusions: We present the case of a hemorrhagic neonatal patient diagnosed with congenital afibrinogenemia and emphasize that fibrinogen testing should be included in the evaluation of such patients. Furthermore, congenital fibrinogen disorders may be more severe when caused due to unknown specific mutation genes. Therefore, a more center-involved genetic analysis is required to identify undiagnosed fibrinogen and fibrinogen mutations.

Congenital afibrinogenemia: Case report of a rare coagulation disorder presenting with scalp hematoma

Congenital afibrinogenemia: Case report of a rare coagulation disorder presenting with scalp hematoma

Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management.

Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.

A homozygous duplication of the FGG exon 8-intron 8 junction causes congenital afibrinogenemia. Lessons learned from the study of a large consanguineous Turkish family.

Congenital afibrinogenemia is the most severe congenital fibrinogen disorder, characterized by undetectable fibrinogen in circulation. Causative mutations can be divided into two main classes: null mutations with no protein production at all and missense mutations producing abnormal protein chains that are retained inside the cell. The vast majority of cases are due to single base pair mutations or small insertions or deletions in the coding regions or intron-exon junctions of FGB, FGA and FGG. Only a few large rearrangements have been described, all deletions involving FGA. Here we report the characterization of a 403 bp duplication of the FGG exon 8-intron 8 junction accounting for congenital afibrinogenemia in a large consanguineous family from Turkey. This mutation, which had escaped detection by Sanger sequencing of short polymerase chain reaction (PCR) amplicons of coding sequences and splice sites, was identified by studying multiple alignments of reads obtained from whole exome sequencing of a heterozygous individual followed by PCR amplification and sequencing of a larger portion of FGG. Because the mutation duplicates the donor splice site of intron 8, we predicted that the impact of the mutation would be on FGG transcript splicing. Analysis of mRNA produced by cells transiently transfected with normal or mutant minigene constructs showed that the duplication causes production of several aberrant FGG transcripts generating premature truncating codons.

Identification of a novel mutation in congenital afibrinogenemia in Iranian patients.

Congenital afibrinogenemia is a rare autosomal recessive disorder that is caused by defects in the fibrinogen. Fibrinogen is a hexameric glycoprotein made of two pairs of three homologous polypeptide chains including Aα, Bβ, and γ that are encoded by three genes named FGA, FGB, and FGG. We aim to study four Iranian families who were referred to our lab for molecular diagnosis of afibrinogenemia. Genomic DNA was extracted from whole blood and Sanger sequencing was performed using primers for all exons and exon-intron junctions of FGA, FGB, and FGG genes. Pathogenicity of the variants was predicted using different in-silico tools and was interpreted according to the American College of Medical Genetics and Genomics guideline. We found three types of mutations in the studied families; two were in the FGA gene and one was in the FGB gene including a nonsense, a novel splicing mutation, and two deletion ones. The nonsense and the deletion mutations may cause a truncated protein and are likely pathogenic and pathogenic, respectively. The novel mutation of splicing found in the FGB gene is a pathogenic one and can break the wild-type acceptor site. Studying mutations in afibrinogenemia patients can expand our knowledge about this disease in Iran.

Pharmacokinetics, surrogate efficacy and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia

Background and aimsCongenital afibrinogenemia is a rare coagulation disorder resulting from a deficiency in fibrinogen. This study assessed the pharmacokinetics, surrogate efficacy and safety of FIB Grifols, a new human plasma-derived fibrinogen concentrate, to treat congenital afibrinogenemia. MethodsEleven adult patients from a multinational, phase 1–2, prospective, open-label, single-arm, uncontrolled clinical study received a single infusion of FIB Grifols, 70 mg/kg bw. Fibrinogen pharmacokinetics (fibrinogen activity: Clauss method; antigen plasma concentrations: ELISA) and efficacy parameters were determined over 14 days after infusion. Efficacy endpoints were the mean change on plasma maximum clot firmness (MCF) on viscoelastic testing and coagulation tests 1-hour post-infusion, and correlation with fibrinogen levels throughout. Safety parameters were also assessed. ResultsFor the Clauss method, (mean [standard deviation]) baseline adjusted Cmax was 1.99 (0.40) g/L, reached 1.76 (1.00) h after infusion, and half-life was 76.94 (20.21) h. Using ELISA, Cmax after FIB Grifols infusion was 2.88 (0.86) mg/mL, with a tmax of 3.06 (2.24) h. Fibrinogen activity and antigen concentrations showed statistically significant correlation of 0.9120 (P < 0.001). Surrogate efficacy was demonstrated by a significant increase of 12.35 (3.85) mm in MCF. Prothrombin time, activated partial thromboplastin time and thrombin time, returned to normal ranges over time, indicating restoration of functionally active fibrinogen. There were no treatment-related adverse events, allergic reactions, serious adverse events, or discontinuations. ConclusionsThe pharmacokinetic profile of functionally active FIB Grifols was established, hemostasis was restored, and FIB Grifols was safe and well tolerated in fibrinogen-deficient patients.

Use of Fibrinogen Determination Methods in Differential Diagnosis of Hypofibrinogenemia and Dysfibrinogenemia.

Fibrinogen plays an important role in hemostasis. The normal concentration of fibrinogen in blood plasma is between 1.8 - 4.2 g/L. Decreased fibrinogen levels are observed in congenital afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, disseminated intravascular coagulation, fibrinolytic therapy, some more severe hepatic parenchymal disorders, and increased blood loss. Elevated fibrinogen levels occur in inflammatory diseases and neoplastic diseases, in pregnancy, and postoperative conditions. Functional fibrinogen measurement is also one of the basic coagulation screening tests. The fibrinogen antigen assay is used to distinguish between qualitative and quantitative fibrinogen disorders. The aim of the study was the use of fibrinogen determination methods in differential diagnosis of hypofibrinogenemia and dysfibrinogenemia, statistical evaluation and determine the relationship of fibrinogen Clauss assay, prothrombin time (PT) derived fibrinogen assay, and fibrinogen antigen in the group of 60 patients with congenital fibrinogen disorders (n = 40 dysfibrinogenemia; n = 20 hypofibrinogenemia). The results measured by the PT-derived fibrinogen assay were approximately four times higher compared to the fibrinogen Clauss assay in the group of patients with dysfibrinogenemia. In patients with hypofibrinogenemia, there is a correlation (r = 0.9016) between the fibrinogen Clauss assay and PT-derived fibrinogen assay with a statistical significance of p < 0.0001. Using a linear or quadratic interpolation function, we were able to determine the fibrinogen Clauss assay and the fibrinogen antigen assay before analysis. The higher level of the PT-derived fibrinogen assay compared to the fibrinogen Clauss assay in the group of patients with dysfibrinogenemia may pose a greater risk to asymptomatic patients who require diagnosis and treatment in case of bleeding. The fibrinogen value using the PT-derived fibrinogen assay could erroneously give a normal level. The use of the interpolation function is important to estimate the value of fibrinogen activity and antigen before the analysis itself by the Clauss assay or analysis by the fibrinogen antigen assay.

Efficacy and safety of fibrinogen concentrate for on-demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency.

BackgroundCongenital fibrinogen deficiency (CFD) is a rare, inherited disorder affecting normal blood clotting function, where patients can experience severe and/or frequent bleeding episodes (BEs). Treatment with human fibrinogen concentrate (HFC) can prevent/arrest bleeding. There is a need for more data on the efficacy, pharmacokinetics (PK) and safety of HFC treatment in paediatric patients with CFD.MethodsHaemostatic efficacy of HFC (Fibryga®, Octapharma AG) for on‐demand treatment of bleeding and surgical prophylaxis in patients <12 years old was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) based on an objective 4‐point efficacy scale. Maximum clot firmness (MCF; surrogate marker of haemostatic efficacy), single‐dose PK and safety were also assessed.ResultsOf 14 patients receiving HFC (median [range] age 6.0 years [1.0–10.0]), eight received HFC for 10 BEs, three for surgical prophylaxis and 13 for PK. The IDMEAC rated haemostatic efficacy as 100% successful for on‐demand BE treatment (95% CI 69.15–100.00) and surgical prophylaxis (95% CI 29.24–100.00). After a mean first dose of 70.78 mg/kg for BEs, mean (±SD) MCF significantly increased from pre‐treatment to 1‐hour post‐infusion (3.3 mm [±1.77]; P = 0.0002), coinciding with haemostatic efficacy. PK parameters were favourable. Two possibly related adverse events occurred, including one serious (portal vein thrombosis). No allergic/hypersensitivity reactions or deaths were observed.ConclusionHFC treatment for on‐demand treatment of BEs and surgical prophylaxis was efficacious for this ultra‐rare paediatric population with congenital afibrinogenaemia and showed a favourable PK and safety profile.

Mutations in the fibrinogen Aα gene account for the majority of cases of congenital afibrinogenemia

AbstractCongenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats. In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the previously identified deletion. Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified. Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia.

Efficacy and Safety of Human Fibrinogen Concentrate for the Treatment of Patients with Congenital Fibrinogen Deficiency: Combined Results of the FORMA-02 and FORMA-04 Clinical Trials

Introduction: Congenital fibrinogen deficiency (CFD) is a rare disorder which results from a complete lack (afibrinogenemia) or low levels (hypofibrinogenemia) of functional fibrinogen. Treatment with human fibrinogen concentrate (HFC) can treat bleeding episodes and prevent blood loss in surgical treatment in patients with CFD. Herein we report combined data from two clinical studies on the efficacy and safety of HFC for the treatment of bleeding episodes (BEs) and surgical prophylaxis in adult, adolescent and pediatric patients. Methods: Both FORMA-02 and FORMA-04 were multinational, multicenter, prospective, open-label, uncontrolled Phase 3 studies for the use of HFC in adult and pediatric patients with CFD. They reported the hemostatic efficacy and safety of human fibrinogen concentrate (HFC: Fibryga® Octapharma) for on-demand treatment of BEs and surgical prophylaxis using objective criteria. Efficacy was assessed by the trial investigators and adjudicated by an independent data monitoring and end-point adjudication committee (IDMEAC). All adverse events (AEs) and serious AEs were recorded. Results: The two studies included a total of 39 patients who received HFC. The median (range) age across both studies was 17 (1-54) years, with 14 pediatric (aged 0-11), 6 adolescent (aged 12-18) and 19 adult patients (aged &amp;gt;18). Treatment of Bleeding Events 32 patients received HFC for the treatment of 99 bleeding events (BEs), 97 minor and 4 major. Of these, 72 were spontaneous, and 27 were due to trauma. 10 BEs occurred in pediatric patients (8 minor, 2 major), and 89 in adult/adolescents (87 minor, 2 major). The mean (±SD) total dose per BE was 65.51 mg/kg (±26.47) for adult/adolescent patients (ages 12-54) and 93.78 (±64.60) for pediatric patients (ages 0-11). Investigator-assessed and IDMEAC rated hemostatic efficacy are shown in Table 1. Overall hemostatic efficacy was rated as success (rating of excellent or good) for 99.0% of BEs by the IDMEAC. Treatment efficacy results were comparable when analyzed by age subgroup of adult (≥18 years), adolescent (&amp;gt;12-&amp;lt;18 years) and in two groups of pediatric patients (&amp;lt;6 years and 6-12 years). Surgical prophylaxis A total of 12 patients received HFC across 15 surgeries (13 minor and 2 major), 3 in pediatric patients (major: splenectomy; minor: circumcision and pulpectomy), and 12 in adults/adolescents (major: eye enucleation with socket reconstruction; minor: knee radioisotope synovectomy [n=2], dental extraction [n=3], circumcision [n=2], excision of circumcision scar bud, root canal operation, skin biopsy, and debridement of superficial necrosis). Mean (±SD) loading dose administered prior to surgery was 77.39 (±20.22) in adult/adolescent patients and 78.50 mg/kg (±27.96) for pediatric patients. Seven surgeries required multiple infusions, with the two major surgeries requiring 5 and 7 maintenance infusions, and the five minor surgeries requiring median (range) 3 (1-4) maintenance infusions. Intra- and post-operative hemostatic efficacy for all surgeries is shown in Table 1. Overall hemostatic efficacy of all the procedures was rated 100% successful by both the investigator and IDMEAC assessment. Safety A total of 101 AEs occurred in 23 patients (59.0%), including 16 serious AEs in 6 patients. Of these, 5 AEs in 4 patients were considered to be possibly related to treatment. These included a mild skin reaction (itchiness and redness), ischemia due to digital microthrombi, peripheral phlebitis of the upper limbs, and a portal vein thrombosis following splenectomy. No allergic/hypersensitivity reactions or deaths were observed during either of the studies. Conclusions: HFC treatment was shown to be efficacious for on-demand treatment of BEs and perioperative prophylaxis in this rare CFD population, across two Phase 3 clinical trials. Efficacy was comparable for adult, adolescent and pediatric patients. A favorable safety profile was seen for the treatment of patients with congenital afibrinogenemia with HFC. Disclosures Djambas Khayat: Octapharma: Research Funding. Kruzhkova:Octapharma: Current Employment. Solomon:Octapharma: Current Employment. Schwartz:Octapharma: Current Employment. Peyvandi:Octapharma: Research Funding. OffLabel Disclosure: On label use: Fibryga for treatment of bleeding episodes Off label use: Use of Fibryga as surgical prophylaxis in the US

A Comprehensive Review of Congenital Platelet Disorders, Thrombocytopenias and Thrombocytopathies.

Platelets play an important role in hemostasis through platelet plug formation by a phenomenon of adhesion; activation; secretion and aggregation. Defects in platelet hemostatic mechanisms can be congenital or acquired. Congenital platelet disorders are rare and manifestations range from asymptomatic to sometimes severe bleeding. The disorders arise due to diverse mechanisms. Congenital platelet disorders include thrombocytopathies and thrombocytopenia (platelet count <150 x 109/L) or thrombocytosis (platelet count > 450 x 109/L). Congenital thrombocytopathies include disorders of adhesion like von Willebrand's disease or Bernard-Soulier syndrome. The disorders of aggregation include congenital afibrinogenemia and Glanzmann thrombasthenia. Disorders of storage granules are gray platelet syndrome and Quebec platelet disorder. Congenital thrombocythopathy and thrombocytopenia often occur in conjunction. In this article, we have a detailed literature review of these rare thrombocytopathies, their presentation and treatment.

Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: FGA, FGB, and FGG (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations.