UNASSIGNED: Congenital fibrinogen disorders are classified based on both fibrinogen levels and the clinical phenotype. For dysfibrinogenemia, normal fibrinogen levels are typical.
UNASSIGNED: We highlight the importance of comprehensive thrombotic risk assessment, including lipoprotein a (Lp[a]) and hypertriglyceridemia in association with severe thrombosis and poor wound healing in dysfibrinogenemia.
UNASSIGNED: We report the case of a 42-year-old male patient with a rare congenital thrombotic-related dysfibrinogenemia (fibrinogen Naples) and multiple thrombotic episodes throughout his life and an unhealing ankle wound. Despite all thrombotic episodes and surgery, the patient had undetectable D-dimer, suggestive of fibrinolytic defect, further supported by over 4-fold elevated Lp(a) levels. The last arterial thrombosis was preoperatively managed by plasma exchange, antithrombotics, and thereafter continued fibrinogen replacement therapy, under which the chronic wound has healed.
UNASSIGNED: The combination of thrombogenesis, abnormal fibrinogen, and high Lp(a) levels is a clinical and research topic deserving more attention.

Congenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and genotype remain poorly defined. This review examines the genetic landscape discovered to date for this rare condition. The question of a possible oligogenic model of inheritance influencing phenotypic heterogeneity is raised, with discussion of the benefits and challenges of sequencing technology used to enhance discovery in this space. Considerable work lies ahead in order to achieve diagnostic and prognostic precision and subsequently provide targeted management to this complex cohort of patients.

BACKGROUND: Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities of fibrinogen. Although the diagnosis of CFDs is based on antigenic and functional level of fibrinogen, few genotypes are clearly correlated with phenotype.
METHODS: In this study, we investigated all of the referred patients diagnosed as CFDs in Taiwan\'s population between 1995 and 2020. Clinical features, laboratory data and genetic defects were analysed. Functional fibrinogen level was determined by the Clauss method. Antigenic fibrinogen was measured by an enzyme-linked immunosorbent assay. Fibrinogen genes were assessed for mutations by polymerase chain reaction and sequencing.
RESULTS: A total of 18 patients from six unrelated families with CFDs were identified. One patient from a consanguineous family was diagnosed as afibrinogenemia type 1A with a novel homozygous frameshift mutation in FGB exon 4. The other five (83.3 %) index patients were all diagnosed as dysfibrinogenemia type 3A caused by two novel and one known mutation. Six (33.3 %) patients from three families had a novel mutation in FGB exon 8. The clinical features and laboratory data were highly variable among these patients with the same mutation.
CONCLUSIONS: Three novel mutations of CFDs causing afibrinogenemia and dysfibrinogenemia were identified. The point mutation in FGB exon 8 is also a common mutation in Taiwan\'s population. Considerable phenotypic variability among the patients with an identical mutation was observed.

Objective: To investigate the clinical type and gene mutations, clinical manifestations, laboratory tests, diagnosis, and fibrinogen replacement therapy of congenital fibrinogen disorders. Methods: Clinical data of 146 patients with congenital fibrinogen disorders diagnosed from April 2000 to November 2020 were retrospectively analyzed. Results: Among the 146 patients, 61 (41.8%) men and 85 (58.2%) women had a median age of 33.5 years at the time of consultation. 34 patients (34.7%) were found to suffer from the disease due to bleeding symptoms, 33 patients (33.7%) due to preoperative examination. 55 patients (56.1%) had at least one bleeding symptom, and 42 patients (42.9%) had no bleeding symptoms. There is a negative correlation between fibrinogen activity concentration and bleeding ISTH-BAT score (rs=-0.412, P=0.001) . A total of 34 gene mutations were detected in 56 patients, of which 84.1% were missense mutations, and 16 new mutations were found. FGA Exon2 and FGG Exon8 mutations accounted for 71.4% of all mutation sites. Patients with afibrinogenemia were younger, with a median age of 2 (1-12) years, an ISTH-BAT score of 4, and patients with dysfibrinogenemia had significantly longer thrombin time (TT) , with a median of 28.5 (19.2-36.6) s. The 1 hour in vivo recovery (IVR) after fibrinogen infusion was (127.19±44.03) %, and the 24 hour IVR was (101.78±43.98) %. In addition to the obvious increase in the concentration of fibrinogen activity, the TT and the prothrombin time (PT) both decreased significantly, and the TT decreased more significantly, with an average decrease of 15.2% compared to the baseline after 24 hours of infusion. Conclusion: Most patients with congenital fibrinogen disorders have mild or no bleeding symptoms. Patients with afibrinogenemia have more severe symptoms. There is a negative correlation between the fibrinogen and the degree of bleeding. Genetic testing is helpful for the diagnosis of disease classification. FIB∶C/FIB∶Ag<0.7 can be used as a basis for clinical diagnosis. The TT can be used as the basis for the diagnosis of dysfibrinogenemia and the effectiveness of fibrinogen infusion.
目的： 探讨先天性纤维蛋白原病的基因突变类型与分型、临床表现、实验室检查、诊断及纤维蛋白原替代治疗情况。 方法： 对2003年4月至2020年11月就诊于中国医学科学院血液病医院的146例先天性纤维蛋白原病患者进行回顾性分析。 结果： 146例患者中，男61例（41.8%），女85例（58.2%），就诊时中位年龄为33.5岁；共采集到98例患者的临床症状学信息，34例（34.7%）因出血症状而就诊，33例（33.7%）因手术前检查而确诊，55例（56.1%）患者至少有1次出血，42例（42.9%）无出血表现。纤维蛋白原活性（FIB∶C）与ISTH-BAT出血评分之间呈负相关（rs=-0.412，P<0.001）。在56例患者中检出34种基因突变（包括新突变16种），其中84.1%为错义突变，FGA外显子2和FGG外显子8突变占全部突变位点的71.4%。无纤维蛋白原血症患者（7例）中位年龄为2（1~12）岁，ISTH-BAT评分为4分；异常纤维蛋白原血症患者（50例）中位凝血酶时间为28.5（19.2~36.6）s。输注纤维蛋白原后1 h、24 h的活性回收率（IVR）分别为（127.19±44.03）%、（101.78±43.98）%。输注纤维蛋白原后，FIB∶C明显提升，凝血酶时间及凝血酶原时间明显下降，用药24 h后凝血酶时间较基线平均下降（15.2±12.1）%。 结论： 多数先天性纤维蛋白原缺乏症患者症状轻微或无症状；无纤维蛋白原血症患者出血症状较为严重，FIB∶C与出血程度之间存在负相关；基因检测有助于疾病分型诊断；FIB∶C/纤维蛋白原抗原（FIB∶Ag）比值<0.7可作为临床分型依据。凝血酶时间可作为异常纤维蛋白原血症诊断及纤维蛋白原替代治疗的疗效判定依据。.

BACKGROUND: We identified a patient with a novel heterozygous variant fibrinogen, γp.C352R (Niigata II; N-II), who had a bleeding episode and failed infertility treatment and was suspected to have hypodysfibrinogenemia based on low and discordant fibrinogen levels (functional assay 0.33 g/L, immunological assay 0.91 g/L). We analyzed the mechanism of this rare phenotype of a congenital fibrinogen disorder.
METHODS: Patient plasma fibrinogen was purified and protein characterization and thrombin-catalyzed fibrin polymerization performed. Recombinant fibrinogen-producing Chinese hamster ovary (CHO) cells were established and the assembly and secretion of variant fibrinogen analyzed by ELISA and western blotting.
RESULTS: Purified N-II plasma fibrinogen had a small lower molecular weight band below the normal γ-chain and slightly reduced fibrin polymerization. A limited proportion of p.C352R fibrinogen was secreted into the culture medium of established CHO cell lines, but the γ-chain of p.C352R was synthesized and variant fibrinogen was assembled inside the cells.
CONCLUSIONS: We demonstrated that fibrinogen N-II, γp.C352R was associated with markedly reduced secretion of variant fibrinogen from CHO cells, that fibrin polymerization of purified plasma fibrinogen was only slightly affected, and that fibrinogen N-II produces hypodysfibrinogenemia in plasma.

We identified a novel heterozygous hypofibrinogenemia, γY278H (Hiroshima). To demonstrate the cause of reduced plasma fibrinogen levels (functional level: 1.12 g/L and antigenic level: 1.16 g/L), we established γY278H fibrinogen-producing Chinese hamster ovary (CHO) cells. An enzyme-linked immunosorbent assay demonstrated that synthesis of γY278H fibrinogen inside CHO cells and secretion into the culture media were not reduced. Then, we established an additional five variant fibrinogen-producing CHO cell lines (γL276P, γT277P, γT277R, γA279D, and γY280C) and conducted further investigations. We have already established 33 γ-module variant fibrinogen-producing CHO cell lines, including 6 cell lines in this study, but only the γY278H and γT277R cell lines showed disagreement, namely, recombinant fibrinogen production was not reduced but the patients\' plasma fibrinogen level was reduced. Finally, we performed fibrinogen degradation assays and demonstrated that the γY278H and γT277R fibrinogens were easily cleaved by plasmin whereas their polymerization in the presence of Ca2+ and \"D:D\" interaction was normal. In conclusion, our investigation suggested that patient γY278H showed hypofibrinogenemia because γY278H fibrinogen was secreted normally from the patient\'s hepatocytes but then underwent accelerated degradation by plasmin in the circulation.

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.

We identified a novel heterozygous variant, Bβp.Pro234Leu (fibrinogen Tokorozawa), which was suspected to be associated with hypofibrinogenemia. Therefore, we analyzed the assembly and secretion of this fibrinogen using Chinese hamster ovary (CHO) cells. To determine the impact on the synthesis and secretion of fibrinogen of the Bβp.P234L and γp.G242E substitutions, we established recombinant variant fibrinogen-producing CHO cell lines. Synthesis and secretion analyses were performed using an enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis with the established cell lines. In addition, we performed fibrin polymerization using purified plasma fibrinogen and in-silico analysis. Both Bβp.P234L and γp.G242E impaired the secretion and synthesis of fibrinogen. Moreover, immunoblotting analysis elucidated the mobility migration of the Bβγ complex in Bβp.P234L. On the other hand, the fibrin polymerization of fibrinogen Tokorozawa was similar to that of normal fibrinogen. In-silico analysis revealed that the Bβp.P234 residue is located in the contact region between the Bβ and γ chains and contacts γp.G242 residue. The present study demonstrated that the Bβp.P234L substitution resulted in hypofibrinogenemia by decreasing the assembly and secretion of fibrinogen. Therefore, there is a possibility that substitutions in the contact region between the Bβ and γ chains impact the assembly and secretion of fibrinogen.

BACKGROUND: 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.
CONCLUSIONS: 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.

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