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      A novel mutation in exon 2 of FGB caused by c.221G>T substitution, predicting the replacement of the native Arginine at position 74 with a Leucine (p.Arg74Leu ) in a proband from a Kurdish family with dysfibrinogenaemia and familial venous and arterial thrombosis

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          Dysfibrinogenaemias may present in either congenital or acquired form and are disorders of fibrinogen structure which may or may not be associated with abnormal function. More than 100 point mutations with single amino acid substitutions have been identified in over 400 families. These lead to defective DNA in the translated fibrinogen molecule. Such cases have improved our understanding of the fibrinogen–fibrin structure. Six members of a consanguineous family including a female proband, a female sibling, three male siblings and a daughter, with ages between 29 years and 53 years presented with early onset venous and premature arterial thromboembolic disease were investigated for a pro-thrombotic tendency associated with dysfibrinogenaemia. The family was investigated using standard coagulation assays and DNA sequencing of the genes encoding the FGA, FGB and FGG. All cases have dysfibrinogenaemia with a fibrinogen level 1.4 to 1.5 (1.9–4.3 g/L). Thrombophilia testing (including AT, PS & PC, F5 G1691A (FV Leiden)/ F2 (prothombin G20210A) genotypes, homocysteine, antiphosphlipid antibody, paroxysmal nocturnal haemoglobinuria by flow cytometry and Janus Kinase-2 (exon 14)) were normal. PCR amplification and sequencing of exon 2 of FBG revealed a heterozygous mutation for a c.221G> T substitution, predicting the replacement of the native Arginine at position 74 with a Leucine (p.Arg74Leu ). In silico analysis of p.Arg74Leu strongly support pathogenicity. A novel mutation was identified in exon 2 of FGB caused by c.221G> T substitution, predicting the replacement of Arginine at position 74 with a Leucine (p.Arg74Leu ) in a proband from a Kurdish family with dysfibrinogenaemia and familial venous and arterial thrombosis.

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          Most cited references 31

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          Natural history of patients with congenital dysfibrinogenemia.

          We conducted a multicenter study of 101 patients with congenital dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean follow-up of 8.8 years after CD diagnosis, the incidence of major bleeding and thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively, with estimated cumulative incidences at age 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and postpartum hemorrhage of 19.8% and 21.4%, respectively. The risk of postpartum hemorrhage was associated with a previously identified bleeding phenotype (odds ratio, 5.8; 95% CI, 1.2 to 28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi vs relatives, sex, mutation hotspots, fibrinogen levels, and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long-term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including postpartum hemorrhage, but also of thrombotic event.
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            Inherited predisposition to thrombosis.

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              Laboratory diagnosis of dysfibrinogenemia.

              Dysfibrinogenemia is a coagulation disorder caused by a variety of structural abnormalities in the fibrinogen molecule that result in abnormal fibrinogen function. It can be inherited or acquired. The inherited form is associated with increased risk of bleeding, thrombosis, or both in the same patient or family. Traditionally, dysfibrinogenemia is diagnosed by abnormal tests of fibrin clot formation; the thrombin time and reptilase time are the screening tests, and the fibrinogen clotting activity-antigen ratio is the confirmatory test. The inherited form is diagnosed by demonstrating similar laboratory test abnormalities in family members, and if necessary by analysis of the fibrinogen protein or fibrinogen genes in the patient. The acquired form is diagnosed by demonstrating abnormal liver function tests and by ruling out dysfibrinogenemia in family members. This article reviews the laboratory testing of dysfibrinogenemia and presents an algorithm for sequential test selection that can be used for diagnosis.

                Author and article information

                0044 20 3312 6806 ,
                J Thromb Thrombolysis
                J. Thromb. Thrombolysis
                Journal of Thrombosis and Thrombolysis
                Springer US (New York )
                3 November 2016
                3 November 2016
                : 43
                : 2
                : 263-270
                ISNI 0000 0001 0693 2181, GRID grid.417895.6, Haemostasis and Thrombosis Unit, Department of Haematology, , Imperial College Healthcare NHS Trust Hospitals, ; St Mary’s Hospital Campus, Praed St, London, W2 1NY UK
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                © Springer Science+Business Media New York 2017


                novel mutation, thrombosis, fibrinogen, dysfibrinogenaemia


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