Clinical And Molecular Pathological Study Of Congenital Dysfibrinogenemia

Congenital dysfibrinogenemia is defined as “the presence in the plasma of qualitatively abnormal,functionally defective fibrinogen” and is an autosomal dominant trait.The defective,non-functioning fibrinogen in circulation causes highly variable clinical presentations and poses great challenges for diagnosis and managements.Most patients are asymptomatic;some of them may experience episodes of bleedings and,counterintuitively,a few patients suffer from thrombotic events.In the current study,102 patients with dysfibrinogenemia from 54 pedigrees were studied and their clinical phenotype and molecular pathogenesis were characterized.We also evaluated prognostic value of thromboelastography?TEG?on clinical manifestation of patients with dysfibrinogenemia and incidents of obstetric complications in non-pregnant female patients.One dysfunctional variant of fibrinogen,Fibrinogen Shanghai,was analyzed in detail to reveal the functional implication of structural change caused by genetic mutation,FGA c.169₁80+2 del.Of all patients studied,68.6% were asymptomatic,27.5% had bleeding symptoms and 3.9% had thrombus formation.Females were more likely to be symptomatic?P=0.01?.Molecular genetic analysis showed that A?Arg35?16?and ?Arg301?275?were two hot-spot mutations with no ethnic difference.Six novel mutations were also identified,including A?Gly33?14?del,FGA c.169₁80+2 del,A?Phe742?723?Tyr,?Asn334?308?Thr,?Gly335?309?Cys and ?Trp395?369?Leu.Patients with mutations at A?Arg35?16?,A?Pro37?18?or A?Arg38?19?had normal outcomes of TEG measurements and the assays also revealed significant functional difference between A?Arg35?16?and ?Arg301?275?related fibrinogen variants?P<0.05?,suggesting that priority of mutation screening at thrombin cleavage site or polymerization site on A? chain may be given if TEG results are normal.Although failed to work as an accurate predictor for patients' clinical presentations,TEG measurement of female patient in nonpregnant state was proved to be a valuable approach to assess their risk of developing obstetric complications when becoming pregnant.ROC analysis demonstrated that K value of 3.8 min,MA value of 54.2 mm,CI value of-3 and MA-CFF value of 12.1 mm were cut-off levels for predicting obstetric complications occurrence,based on Youden index analysis.In addition,MA-CFF showed to have a better prognostic performance than the other three parameters for predicting obstetric complications occurrence,with a corresponding area under ROC curve?AUROC?of 0.923?range 0.815-1.031,p=0.001?.Significantly high odds ratio?OR?of obstetric complications occurrence were demonstrated in K?3.8 min,MA?54.2 mm,CI?-3 and MA-CFF?12.1 mm?p<0.05?in TEG assays.In the current study,a novel heterozygous variant?FGA c.169₁80+2 del?was identified in one dysfibrinogenemia patient with recurrent venous thrombosis and antiphospholipid antibody syndrome?APS?.Pedigree investigation revealed that the patient had this trait inherited from his asymptomatic father.Our study showed that the mutation FGA c.169₁80+2 del led to an aberrant exon 2-skipped mRNA transcript and caused N terminal non-framshift deletion of 42 amino acids in A? chain.This heterozygous variant does not interfere with assembly or secretion of fibrinogen,but compromises fibrin polymerization and clot formation.The results of clot lysis using plasma sample indicate that APS at least partially contributes to the development of thrombosis in the propositus.