Clinical features and molecular basis of 102 Chinese patients with congenital dysfibrinogenemia

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Abstract

Introduction

Congenital dysfibrinogenemia (CD) is a rare qualitative disorder of fibrinogen (Fg) with heterogeneous clinical manifestations. We aimed to analyze clinical phenotype and molecular basis of 102 Chinese CD patients and to evaluate the application of thromboelastography (TEG).

Materials and methods

Clinical manifestations were recorded and quantified using the consensus ISTH bleeding assessment tool. Kaolin activated TEG and functional Fg TEG were applied in 30 patients. Genetic analysis of Fg genes were performed by direct sequencing.

Results

27.5% patients experienced bleeding, 3.9% had thrombosis and 68.6% were asymptomatic. Females were more prone to experience bleeding (P = 0.01). Significant difference (P < 0.05) in TEG results were found between patients with hot-spot mutations at AαArg35(16) and γArg301(275), but were not identified between patients with and without bleeding. Normal TEG results were found in patients with mutations at AαArg35(16), AαPro37(18) or AαArg38(19). Six novel mutations were identified, including AαGly33(14)del, AαAsp57(38)_Trp60(41)delIVS2 + 1_ + 2GTdel, AαPhe742(723)Tyr, γAsn334(308)Thr, γGly335(309)Cys and γTrp395(369)Leu.

Conclusions

CD patients have similar clinical manifestations and hot-spot mutations worldwide with no ethnic difference. TEG results could not indicate the bleeding risk in patients, but priority of mutation screening at thrombin cleavage site or polymerization site on Aа chain may be given if TEG results are normal.

Introduction

Fibrinogen (Fg) is a 340 kDa glycoprotein playing key roles in fibrin clot formation, non-substrate thrombin binding, platelet aggregation and fibrinolysis [1]. It is composed of three pairs of non-identical chains (Aα, Bβ, γ)2, which are encoded by FGA, FGB and FGG genes, respectively, clustered in a region of 50 kb on 4q31. Upon activation of the coagulation cascade, fibrin is produced by proteolytic cleavage of the fibrinogen Aα and Bβ chains by thrombin, thus releasing fibrinopeptides A and B and allowing polymerization to occur [1]. Activated factor XIII (FXIIIa) mediated cross-linking stabilizes this network into a covalently-linked fibrin clot [2].

Congenital fibrinogen disorders are rare and affect either quantity (afibrinogenemia and hypofibrinogenemia) or function (dysfibrinogenemia) of circulating fibrinogen, or both (hypo-dysfibrinogenemia). To date, more than 400 cases of congenital dysfibrinogenemia (CD) have been reported [3]. The clinical manifestations of dysfibrinogenemia are heterogeneous. Nearly 55% of them were asymptomatic, 30% of them experienced bleeding and 15% of them had thrombosis [4], [5]. The majority of dysfibrinogenemia defects, inherited as a dominant trait, are caused by heterozygous missense mutations in one of the three fibrinogen genes, which may impair conversion to fibrin monomer or affect critical interactions between fibrin and FXIIIa, fibrinolysis mediators or cell-surface integrins [6]. Only a few of dysfibrinogenemias are caused by homozygous mutations and most of patients in this kind are symptomatic [3].

Global assays, such as thromboelastography (TEG), have been shown to have potential providing a better evaluation of haemostatic state in individuals. Common TEG applications include assessment and decision making for fibrinolytic and anticoagulant therapies and for transfusion for acute blood loss [7]. Functional fibrinogen TEG (FF-TEG), which eliminates the contribution of platelets to clot strength, is special to evaluate all aspects of Fg function reflected by maximum amplitude (MA-CFF). Moderate correlations between fibrinogen level measured by Clauss assay (Fg:C) and MA measured by kaolin activated TEG or MA-CFF measured by FF-TEG have been identified both in healthy volunteers and in patients operated for ischemic heart disease without known coagulopathy or hepatopathy [8], [9], [10]. Mutant fibrinogen purified from the plasma of dysfibrinogenemia patients were shown to affect the signal generation of TEG [11]. However, the evaluation of the whole blood sample from dysfibrinogenemia patient using TEG has not been reported.

In this study, we analyzed clinical phenotype and molecular basis of 102 Chinese patients with CD. In addition, the potential application value of TEG in CD patients was also evaluated.

Section snippets

Study population

A total of 102 patients enrolled between 2005 and 2014 in Shanghai Ruijin Hospital were studied on informed consent. CD was diagnosed by low Fg:C with normal antigen level of Fg (Fg:Ag), combined with molecular defect identified in one of the three fibrinogen genes. Clinical manifestations were recorded in a standard questionnaire and were quantified using the consensus ISTH BAT. These were compared to bleeding scores determined from an age- and sex-matched group of health volunteers (n = 50; 25

Demographic and clinical characteristics

Our cohort included 102 cases (53 males and 49 females) from 54 families (54 propositi and 48 relatives) with a median age of 35 (range 3–76). Propositi were diagnosed with CD at the similar ages with their relatives (35.9 yr compared to 37.5 yr, P > 0.05). Most of propositi (44/54) were diagnosed during the routine investigation before surgery and only 10 propositi were identified during the investigation of bleeding (7 cases) and thrombosis (3 cases).

The overall ISTH-BAT scores in participants

Discussion

We reported a study of 102 Chinese patients with CD. Most patients (68.6%) were asymptomatic, similar to the 48% reported by Shapiro et al. [5]. The main clinical association was abnormal bleeding with an incidence of 27.5%, which is close to 34% reported by Shapiro et al. but is lower than 47.5% reported by Casini et al. from a follow-up study for 8 years [14]. However, the incidence of major bleeding events at the time of CD diagnosis in our study (10.8%) was similar to that in the study done

Authorship contributions

Jingyi Zhou designed the study, recruited and interviewed participants, collected blood, performed haemostatic assays, TEG assays and genetic analysis, reviewed and interpreted data, and wrote the manuscript. Qiulan Ding supervised research, helped to design the study and critically revised the manuscript. Yaopeng Chen recruited and interviewed participants, collected blood and performed hemostatic assays. Qi Ouyang and Linlin Jiang recruited and interviewed participants, collected blood and

Disclosure of conflict of interests

The authors state that they have no conflict of interest.

Acknowledgments

We thank the patients and family members for their interest and support of this study. This study was supported by the National Basic Research Program of China (2013CB966800), the General Program of National Natural Science Foundation of China (30770904 and 81170480) and Doctoral Innovation Fund Projects from Shanghai Jiaotong University School of Medicine (BXJ201412).

References (31)

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