Clinical observation of hypofibrinogenemia induced by the treatment of tocilizumab in rheumatic diseases and exploration of risk factor for hypofibrinogenemia.

OBJECTIVE: The objective of this study was to analyze the changes in plasma fibrinogen (FIB) levels during tocilizumab (TCZ) treatment in patients with rheumatic diseases, to clarify the incidence of hypofibrinogenemia and its possible risk factors, and to establish a nomogram model for predicting the probability of hypofibrinogenemia in rheumatoid arthritis (RA) patients treated with TCZ. METHODS: Clinical data of patients treated with TCZ at the Department of Rheumatology and Immunology, the First Affiliated Hospital of Xi'an Jiaotong University from January 2014 to October 2021 were retrospectively analyzed to observe the incidence of hypofibrinogenemia in several rheumatic diseases at different time points. The risk factor of hypofibrinogenemia in RA patients treated with TCZ was determined by using Cox regression analysis. Based on the results of Cox regression analysis, a nomogram for predicting the probability of hypofibrinogenemia in rheumatoid arthritis (RA) patients treated with TCZ was established and validated through RStudio software. RESULTS: A total of 83 TCZ-treated patients were enrolled in this study, and 32 (38.55%) patients developed hypofibrinogenemia during TCZ treatment. There were 8 males and 24 females in the FIB-reduced group, with an average age of 44.88 ± 18.39 years. Hypofibrinogenemia was most common in TCZ-treated patients with takayasu arteritis (TA) and RA. Hypofibrinogenemia typically occured within 3 months after TCZ treatment. In RA patients treated with TCZ, platelet distribution width, parathyroid hormone, bone mineral density, tender joint count, and swollen joint count were independent risk factors for the occurrence of hypofibrinogenemia. The nomogram based on the above risk factors could effectively predict the probability of hypofibrinogenemia in RA patients receiving TCZ. CONCLUSION: Although bleeding symptoms were not observed in this study, the incidence of hypofibrinogenemia remained high after TCZ treatment, usually occurring within 3 months of treatment. Therefore, it is necessary to monitor FIB levels during TCZ treatment. In addition, clinicians can use the nomogram model developed from this study to predict the incidence of hypofibrinogenemia after TCZ treatment in RA patients. Key Points • Hypofibrinogenemia often occurs during TCZ treatment for rheumatic diseases. • PDW, PTH, BMD, tender joint count, and swollen joint count are risk factors for the occurrence of hypofibrinogenemia. • It is necessary to monitor FIB levels during TCZ treatment to avoid bleeding tendency.

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.

ABSTRACT: Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

Obstetrical complications in hereditary fibrinogen disorders: the Fibrinogest study.

BACKGROUND: Women with hereditary fibrinogen disorders (HFDs) seem to be at an increased risk of adverse obstetrical outcomes, but epidemiologic data are limited. OBJECTIVES: We aimed to determine the prevalence of pregnancy complications; the modalities and management of delivery; and the postpartum events in women with hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia. METHODS: We conducted a retrospective and prospective multicentric international study. RESULTS: A total of 425 pregnancies were investigated from 159 women (49, 95, and 15 cases of hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia, respectively). Overall, only 55 (12.9%) pregnancies resulted in an early miscarriage, 3 (0.7%) resulted in a late miscarriage, and 4 (0.9%) resulted in an intrauterine fetal death. The prevalence of live birth was similar among the types of HFDs (P = .31). Obstetrical complications were observed in 54 (17.3%) live birth pregnancies, including vaginal bleeding (14, 4.4%), retroplacental hematoma (13, 4.1%), and thrombosis (4, 1.3%). Most deliveries were spontaneous (218, 74.1%) with a vaginal noninstrumental delivery (195, 63.3%). A neuraxial anesthesia was performed in 116 (40.4%) pregnancies, whereas general or no anesthesia was performed in 71 (16.6%) and 129 (44.9%) pregnancies, respectively. A fibrinogen infusion was administered in 28 (8.9%) deliveries. Postpartum hemorrhages were observed in 62 (19.9%) pregnancies. Postpartum venous thrombotic events occurred in 5 (1.6%) pregnancies. Women with hypofibrinogenemia were at an increased risk of bleeding during the pregnancy (P = .04). CONCLUSION: Compared with European epidemiologic data, we did not observe a greater frequency of miscarriage, while retroplacental hematoma, postpartum hemorrhage, and thrombosis were more frequent. Delivery was often performed without locoregional anesthesia. Our findings highlight the urgent need for guidance on the management of pregnancy in HFDs.

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

INTRODUCTION: 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. METHODS: We performed a retrospective study on Egyptian children with congenital afibrinogenaemia who experienced ICH, in order to estimate frequency, symptoms and neurological outcomes. RESULTS: 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 1 year (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 24 h 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). CONCLUSION: 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.

Clinical and molecular characterization of Iranian patients with congenital fibrinogen disorders.

INTRODUCTION: Congenital fibrinogen disorders (CFDs) are caused by mutations in the FGA, FGB and FGG genes and are classified as quantitative and qualitative fibrinogen defects. This study sought to determine the genetic background of CFDs in Iran and to examine the genotype-phenotype correlation. METHODS: Fourteen patients with a CFD diagnosis were included. Fibrinogen antigen and activity were measured by the immunoturbidimetric and Clauss methods respectively. Gene sequencing was performed following a polymerase chain reaction amplification of fibrinogen's genes. The ISTH Bleeding Assessment Tool was also evaluated for all cases. RESULTS: Patients were diagnosed with dysfibrinogenemia (n = 10), hypodysfibrinogenemia (n = 2) and afibrinogenemia (n = 2). Seven different mutations located on FGA exon 2 (57 %), exon 4 (7%), exon 5 (7%) and FGG exon 8 (29 %) were identified. In patients with qualitative deficiencies, mutations were including p.Arg38Thr, p.Arg35His, p.Arg35Cys, p.Val145Asp, and p.Arg301Cys and were including p.Gly316GlufsX105 and p.Trp52stop in afibrinogenemic patients. In dysfibrinogenemia, two hotspot mutations, FGA Arg35 and FGG Arg301 were identified in 60 % of patients and the remaining (40 %) had p.Arg38Thr mutation. The p.Val145Asp and two hotspot mutations, p.Arg35His, p.Arg35Cys, were identified for the first time in Iran. The overall median (range) bleeding score (BS) was 4 (0-6) in all patients and it was 3.5 (0-5) in dysfibrinogenemia. Cutaneous bleeding and menorrhagia were the most common bleeding manifestations. CONCLUSION: There was a weak genotype-phenotype correlation in CFDs and patients with dysfibrinogenemia were more symptomatic than in previous studies. Despite ethnic's differences, the prevalence of hotspot mutations in dysfibrinogenemia was similar to the other studies.

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, Bß, 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.

Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management.

Fibrinogen is a complex protein playing a major role in coagulation. Congenital afibrinogenemia, characterized by the complete absence of fibrinogen, is associated with major hemostatic defects. Even though the clinical course is unpredictable and can be completely different among patients, severe bleeding is the prominent symptom. Patients are also at increased risk of thrombosis and sometimes suffer from spontaneous spleen rupture, bone cysts and defective wound healing. Due to the relative rarity of afibrinogenemia, there are no evidence-based strategies for helping physicians in care of these patients. Fibrinogen supplementation is the keystone to prevent or treat bleeding events. In addition, fibrinogen, a pleiotropic protein with numerous physiological roles in immunity, angiogenesis and tissue repair, is involved in many diseases. Indeed, depletion of fibrinogen in animal models of infections, tumors and neurological diseases has an effect on the clinical course. The consequences for patients with afibrinogenemia still need to be investigated.

Screening method for congenital dysfibrinogenemia using clot waveform analysis with the Clauss method.

INTRODUCTION: Congenital fibrinogen disorders (CFDs) are classified as afibrinogenemia or hypofibrinogenemia (Hypo), dysfibrinogenemia (Dys), or hypodysfibrinogenemia (Hypodys), according to functional and antigenic fibrinogen concentrations. However, in routine laboratory tests, plasma fibrinogen levels are mostly measured using the functional Clauss method and not as an antigenic level. Therefore, it is difficult to discriminate CFD from acquired hypofibrinogenemia (aHypo). To establish a screening method for CFD, we investigated the parameters of clot waveform analysis (CWA) from the Clauss method. METHODS: We compared fibrinogen concentrations determined using Clauss and prothrombin time (PT)-derived methods for 67 aHypo and CFD cases (19 Dys, 4 Hypodys, and 1 Hypo determined using antigen levels and DNA sequence analysis) with a CS-2400 instrument, and the CWA parameters, dH and Min1, were analyzed automatically with an on-board algorithm. dH and Min1 are the maximum change in transmittance at the end of coagulation and the maximum velocity of transmittance change during coagulation, respectively. RESULTS: Clauss/PT-derived ratios detected 18 cases of Dys and Hypodys but no Hypo cases, whereas Clauss/dH plus Clauss/Min1 ratios were calculated from fibrinogen concentration using the Clauss method and CWA parameters detected 21 cases of Dys and Hypodys and one Hypo case. Moreover, the Clauss/PT-derived ratio and Clauss/dH plus Clauss/Min1 ratio detected 22 cases of Dys and Hypodys cases and one Hypo case. CONCLUSION: This report demonstrates that CWA parameters of the Clauss method, Clauss/dH plus Clauss/Min1 ratio, screened Dys patients with a higher rate, whereas Clauss/PT-derived ratios did not.

Hereditary Hypofibrinogenemia with Hepatic Storage.

Fibrinogen is a 340-kDa plasma glycoprotein constituted by two sets of symmetrical trimers, each formed by the Aα, Bß, and γ chains (respectively coded by the FGA, FGB, and FGG genes). Quantitative fibrinogen deficiencies (hypofibrinogenemia, afibrinogenemia) are rare congenital disorders characterized by low or unmeasurable plasma fibrinogen antigen levels. Their genetic basis is represented by mutations within the fibrinogen genes. To date, only eight mutations, all affecting a small region of the fibrinogen γ chain, have been reported to cause hereditary hypofibrinogenemia with hepatic storage (HHHS), a disorder characterized by protein aggregation in the endoplasmic reticulum, hypofibrinogenemia, and liver disease of variable severity. Here, we will briefly review the clinic characteristics of HHHS patients and the histological feature of their hepatic inclusions, and we will focus on the molecular genetic basis of this peculiar type of coagulopathy.

Risk factors for tigecycline-induced hypofibrinogenaemia.

WHAT IS KNOWN AND OBJECTIVE: Hypofibrinogenaemia is major treatment-related adverse event associated with tigecycline therapy, which in some cases can result in treatment termination. We aimed to identify the risk factors for tigecycline-induced hypofibrinogenaemia. METHODS: We retrospectively retrieved 426 Chinese patients who were undergoing tigecycline therapy ≥ 3 days. RESULTS AND DISCUSSION: There were 426 patients treated with tigecycline. The mean age was 60.31 ± 19.23 years, and 299 (70.19%) patients were male. Of the patients, 50.5% developed hypofibrinogenaemia and 10.1% of patients developed bleeding. Compared with before treatment, fibrinogen (FIB) significantly decreased after tigecycline was used while prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) significantly increased (all P < .001). There was no statistically significant difference in platelet count, hepatic function, and renal function before and after tigecycline treatment (all P > .05). In analysing relevant risk factors, extension of the tigecycline treatment course was found to be the main risk factor for tigecycline-induced hypofibrinogenaemia. Regardless of whether patients received the standard dose or high dose of tigecycline, the long treatment course group (>14 days) had more patients with hypofibrinogenaemia than the routine treatment course group (52.21% vs 40.74%, 48.81% vs 19.44%, all P < .05). Renal failure (whether requiring or not requiring dialysis) is also a risk factor for tigecycline-induced hypofibrinogenaemia (OR [95% CI]: 2.450 [1.335-4.496]). WHAT IS NEW AND CONCLUSION: Tigecycline administration has been related to hypofibrinogenaemia, especially patients with renal failure and when long treatment course of tigecycline are used. We recommend that coagulation function be closely monitored in patients with the aforementioned risk factors for tigecycline-induced hypofibrinogenaemia to ensure patient safety.

Clinical characteristics and risk factors of tigecycline-associated hypofibrinogenaemia in critically ill patients.

PURPOSE: To analyze the clinical features and risk factors of tigecycline-associated hypofibrinogenaemia and study whether cefoperazone/sulbactam combined with tigecycline aggravates coagulopathy or hypofibrinogenaemia. METHODS: A retrospective case-control study of patients with severe infection who were treated with tigecycline was conducted. Patients were assigned to the hypofibrinogenaemia group (< 2.0 g/L) and normal fibrinogen (normal) group (≥ 2.0 g/L) to assess the clinical features of patients with tigecycline-associated hypofibrinogenaemia. The traits of patients treated with cefoperazone/sulbactam in the hypofibrinogenaemia group were also analyzed. RESULTS: In total, 127 patients were enrolled in the study, including 71 patients with hypofibrinogenaemia and 56 patients with normal fibrinogen levels. Hypofibrinogenaemia developed at a median of 6 (4-8) days after tigecycline treatment, and the fibrinogen level returned to normal at a median of 3 (3-5) days after tigecycline discontinuation. In the multivariate analysis, intra-abdominal infection (p = 0.005), fibrinogen level at tigecycline initiation (p < 0.001), maintenance dose (p = 0.039), and treatment duration (p = 0.002) were found to be related to hypofibrinogenaemia. Treatment with cefoperazone/sulbactam was not associated with hypofibrinogenaemia (p = 0.681), but patients treated with cefoperazone/sulbactam had a higher incidence of coagulopathy (p = 0.009) and needed more blood products (p = 0.003) than those treated without cefoperazone/sulbactam. CONCLUSION: Tigecycline-associated hypofibrinogenaemia often developed on the 6th (4th-8th) day of tigecycline use and was associated with intra-abdominal infection, fibrinogen level at tigecycline initiation, maintenance dose, and treatment duration of tigecycline but not cefoperazone/sulbactam.

Genetic Analysis of Afibrinogenemia and Hypofibrinogenemia: Novel Mutations in the FGB Gene in the Turkish Population.

INTRODUCTION: Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Hypofibrinogenemia is characterized by fibrinogen levels <1.5 g/L. OBJECTIVE: In this study, we analyzed fibrinogen beta chain gene mutations in Turkish afibrinogenemia and hypofibrinogenemia patients. METHODS: We evaluated 20 afibrinogenemia and hypofibrinogenemia patients and 80 healthy controls. We have sequenced all exons of the FGB gene using the DNA isolated from the peripheral blood samples of patients and controls. RESULTS AND CONCLUSION: We found a nonsense mutation in exon 4 at nucleotide 630 that encoded serine amino acid, and in the same exon a missense mutation of T to C at nucleotide 647, resulting in a transition from leucine to proline (p.L198P) in a child with hypofibrinogenemia. These mutations have been shown for the first time in the same patient of Turkish descent. Furthermore, there was a novel heterozygous guanine-to-adenine nucleotide change in exon 3. This caused the change of arginine amino acid to threonine amino acid at position 136 (p.A136T) in a protein, which has not been described in the literature before.

Comparison of clinical phenotype with genetic and laboratory results in 31 patients with congenital dysfibrinogenemia in northern Slovakia.

Congenital dysfibrinogenemia (CD) is a rare disorder of hemostasis. The majority of cases are caused by heterozygous missense mutations in one of the three fibrinogen genes. Patients with CD may experience bleeding and thrombosis, but many are asymptomatic. To better describe the clinical, laboratory, and genotypic picture of CD, we evaluated 31 patients from seven unrelated families using standard coagulation tests and genetic analysis. The clinical phenotype consisted of bleeding in 13/31 (42%) patients; other patients (18/31; 58%) were asymptomatic. Among patients with bleeding, symptoms were mostly in single anatomical sites, with variable intensity of bleeding. Compared to results from a previous large systematic survey, our results showed a similar mean bleeding score, but a higher incidence of bleeding episodes without thrombotic complications. In the present study, we identified three known pathogenic point mutations in the FGA (c.95G > A, c.104G > A) and FGB (c.586C > T) genes. The variants of CD identified in this cross-sectional study were either asymptomatic or had bleeding manifestations and showed similar laboratory features, irrespective of genotype. Results from genetic and clinical studies will continue to yield valuable information on the structure and function of the fibrinogen molecule.

Congenital structural and functional fibrinogen disorders: a primer for internists.

Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on chromosome 4q28. It is estimated that congenital fibrinogen disorder accounts for 8% of rare coagulation factor deficiencies. Most of congenital fibrinogen disorders are suspected in individuals with bleeding tendency or coincidentally discovered, for instance prior to surgery. Fibrinogen disorders could be also found in patients with thrombotic events, impaired wound healing, and recurrent spontaneous abortions. Afibrinogenemia manifests as mild to severe bleeding, while hypofibrinogenemia is often asymptomatic. Dysfibrinogenemia, a qualitative fibrinogen disorder, is associated with bleeding, thrombosis, or with no symptoms. Recent recommendations issued by the International Society on Thrombosis and Haemostasis in 2018 do not encourage routine evaluation of thrombin time or other coagulation tests in patients with suspected congenital fibrinogen disorders, highlighting the value of fibrinogen antigen measurement and genetic analysis, added to the key finding, that is, reduced fibrinogen concentration determined with a coagulometric assay. The current review summarizes practical issues in diagnostic workup and clinical management of patients with afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia from a perspective of internists who may encounter patients with reduced fibrinogen concentration in everyday practice. Despite the fact that hematologists are in front line for the management of patients with bleeding tendency, internists should be aware of the clinical and laboratory findings in patients with inherited fibrinogen disorders including the risk of thromboembolism and management prior to invasive procedures.

Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: Identification of three novel fibrinogen gamma chain mutations.

INTRODUCTION: Congenital fibrinogen disorders are poorly explored in Slavic populations. The aim of this study was to characterize the genetic background and clinical manifestations of fibrinogen disorders in the Polish case series. MATERIALS AND METHODS: In 27 unrelated patients (mean [SD] age, 30.4 [19.2] years, 30% men) with fibrinogen concentration (von Clauss method) < 1.8 g/L, exons and intron-exon junctions of the fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG) genes were analyzed using polymerase chain reaction (PCR) amplification followed by sequencing. RESULTS: At enrollment, 15 (55.6%) and 2 (7.4%) of patients experienced bleeding and thrombotic events, respectively, and the remainder were asymptomatic. The following congenital fibrinogen disorders were identified: 1A. afibrinogenemia, n = 1; 2A. severe hypofibrinogenemia, n = 2; 2B. moderate hypofibrinogenemia, n = 4; 2C. mild hypofibrinogenemia, n = 6; 3A. dysfibrinogenemia, n = 12; 3B. thrombotic related-dysfibrinogenemia, n = 1; 4C. mild hypodysfibrinogenemia, n = 1. Eight dysfibrinogenemic patients (62%) were carriers of hotspot mutations. Fifteen patients were heterozygous and one (afibrinogenemia) homozygous for known causative mutations. Three new heterozygous mutations were detected, all affecting splicing in FGG: fibrinogen Poznan II, a 177 bp deletion eliminating parts of intron 6 and exon 7 in a dysfibrinogenemic woman with recurrent bleeding; fibrinogen Zakopane, (intron 2 acceptor splice site) and fibrinogen Belchatow (intron 1 donor splice site), found in hypofibrinogenemic patients. During follow-up (median 60, interquartile range 10-60 months), bleeding episodes, mainly menorrhagia and easy bruising were reported in 15 (55.6%) patients. One thromboembolic event was observed. CONCLUSION: This study of the largest cohort of Slavic patients with congenital fibrinogen disorders has enabled the identification of 3 new FGG mutations and shows a high prevalence of bleeding manifestations with recurrences.

Risk of bleeding and thrombosis in inherited qualitative fibrinogen disorders.

OBJECTIVES: Inherited dysfibrinogenemia is a rare disorder, for which clinical studies related to the risk of bleeding or thrombosis and the type of causative mutation are scanty. MATERIALS AND METHODS: We analyzed the laboratory, clinical, and genotypic features of 50 patients with inherited dysfibrinogenemia belonging to 19 unrelated families. RESULTS: In all the index cases, fibrinogen activity by Clauss method was below the normal range, while it was observed in 57.9% only by PT-derived method. In three families, hypodysfibrinogenemia was evident, associated with three novel mutations (Ter492Gln in FGB, Cys365Asp, and Leu370Phe in FGG). Three additional novel mutations were also identified (Arg114Lys in FGA, Ile131Thr and Trp234Arg in FGG). Bleeding symptoms assessed by ISTH-BAT scored at least 1 in 30% of patients and, significant bleeding symptoms were mainly present in female patients, especially associated with pregnancy. Two patients with FGB Arg44Cys suffered from venous thromboembolism, and two with FGA Arg35His had ischemic stroke at older age. CONCLUSIONS: This study confirms the heterogeneity of clinical features in inherited dysfibrinogenemia, due to the wide spectrum of the causative mutations. Larger multicenter studies are needed to assess the definitive correlation of some mutations with bleeding or thrombosis.

Mutational Epidemiology of Congenital Fibrinogen Disorders.

BACKGROUND: Numerous mutations in FGA, FGB or FGG lead to congenital fibrinogen disorders (CFDs), but their epidemiology is not well characterized. The aim of this study was to evaluate the molecular epidemiology of CFD and to develop a genotyping strategy. METHODS: Genetic data from 266 unrelated CFD patients genotyped at our laboratory and from a CFD open access database (n = 1,142) were evaluated. We developed a step-wise screening strategy for the molecular diagnosis of CFD and prospectively tested this strategy on 32 consecutive CFD probands. RESULTS: We identified 345 mutated alleles overall, among 187 heterozygous, 63 homozygous and 16 compound heterozygous individuals. Afibrinogenemia was almost always caused by null mutations (98.6%), mainly in FGA (85%). Hypofibrinogenemia was mainly caused by missense mutations of FGB or FGG (54.2%). Dysfibrinogenemia was almost always caused by heterozygous missense mutations (99.3%) in FGA and FGG. Hotspot mutations were prevalent among quantitative (33.1%) and qualitative fibrinogen disorders (71.1%). The mutational cluster at our laboratory was similar with that reported in the CFD open access database. The proposed step-wise genetic screening strategy proved efficient in both the development and validation samples for CFD: the screening of FGA exons 2, 4, 5 and FGG exon 8 and search for the 11 kb deletion of FGA led to the identification of approximately 80% of mutated alleles, including 15 new mutations. CONCLUSION: The described molecular epidemiology of CFD is complex. The proposed step-wise genetic screening strategy may provide an efficient way to identify causative mutations analysing a minimal number of exons.