Abstract Number: PB0719
Meeting: ISTH 2020 Congress
Background: Congenital qualitative fibrinogen disorders include dysfibrinogenemia (DF) with decreased functional and normal antigenic fibrinogen levels, and hypodysfibrinogenemia (HDF) with discrepant decrease of functional and antigenic fibrinogen levels. Most of patients are asymptomatic, but a bleeding, generally mild, and thrombosis could be present. Its prevalence is low and underestimate.
Aims: To describe a case series of qualitative fibrinogen disorders with their mutations found in Argentina.
Methods: Fibrinogen (FBG) were measured by Clauss Method (FBG-C). Immunologic FBG by radial-immunodiffusion technique (FBG-RID). Prothrombin Time derived FBG (FBGPTd). Thrombin Time (TT) and Reptilase Time (RT) were performed. Thromboelastometry ROTEM® Delta: FIBTEM MCF and EXTEM was recorded. Genetic studies: PCR Amplification and Sanger Sequences for the three FBG genes were also performed. We present the results found in 8 patients from 4 different centers in Argentina and 6 of their relatives.
Results: Patients characteristics, phenotypic expression, clinical manifestations and laboratory results are included in table 1. Two patients were asymptomatic, and the diagnosis was a laboratory finding. Three patients presented mild bleeding, one thrombosis and severe bleeding, one aortic valve thrombosis and one acute myocardial infarction. Three unrelated patients presented the same mutation (AαGly33(14)del), previously reported in China. Two patients presented “hotspot” mutations, and two unidentified mutations were found (one with thrombotic HDF, and the other with DF and mild bleeding). Only in one of the relatives studied we found the same mutation of the father.
Conclusions: Genetic defects found in the FBG genes could explain the discrepancy between levels of antigenic FBG and FBG-C. Two novels mutations and only few “hotspot” mutations were found in our case series. Most patients present normal or even increased viscoelastic fibrinogen assessment. Few patients with mild bleeding manifestations (only one severe bleeding), two asymptomatic and some patients with thrombotic manifestations were found, reflecting the phenotypic variability interpatient described in the literature.
|Patient (Sex, Age)||Phenotype Clinical Manifestations||FBG-C mg/dL||FBG-RID mg/dL||FBGPTd mg/dL||TT sec||RT sec||ROTEM MCF (mm)||Genetic studies||Relatives studied|
|BOB MAT (M, 24)||DF Asymptomatic||52||388||285||30||30||Normal EXTEM||Heterozygous for AαGly33(14)del||–|
|DEL CRIS (F, 36)||DF Asymptomatic||67||251||363||32||23||Normal EXTEM||Heterozygous for AαGly33(14)del||–|
|PAS CLA (M, 63)||DF, Arterial thrombosis and severe bleeding||109||546||609||29||30||FIBTEM 61||Heterozygous for AαGly33(14)del||–|
|BUL ALI (F, 66)||DF, Mild bleeding||72||388||430||24||54||FIBTEM 15||Heterozygous for a previously unidentified mutation in FGA exon2:c. 106G>C Gly36Arg (Gly17Arg without the signal peptide)||Daughter: normal FGA Gly36|
|REI FAC (M, 38)||HDF, Aortic valve thrombosis and stroke||59||114||224||27||37||FIBTEM 4||Heterozygous for a previously unreported missense mutation in FGG exon 8: Tyr375Cys (Tyr349Cys in the mature gamma chain lacking the signal peptide)||Parents and sister: all normal FGG Tyr375|
|LUN PAB (M, 48)||DF, Mild bleeding post-surgery||56||190||214||30||24||FIBTEM 11||Heterozygous for FGA exon 2 c.96_98 del AGG, del Gly 33 (del Gly 14 in the mature chain without the signal peptide).||Daughter: Heterozygous for FGA exon 2 c.96_98 del AGG, del Gly 33 (del Gly 14 in the mature chain without the signal peptide).|
|RAM LAM (M, 79)||DF, Mild bleeding||45||373||240||35||>120||FIBTEM 8||Heterozygous for “hotspot” in FGA exon 2 c.103C>T, Arg35Cys||–|
|GER OMA (M, 76)||DF, AMI||90||No result||No result||21||22||FIBTEM 4||Heterozygous for a common “hotspot” dysfibrinogenemia mutation in FGG exon 8, Arg301Cys (Arg275Cys without the signal peptide)||Grand daughter: normal FGG Arg301|
|Reference range||–||180-400||150-400||200-400||14-18||15||FIBTEM 9-25||–||–|
[TABLE 1. Patients investigated with the mutations found. DF: Dysfibrinogenemia, HDF: Hypodysfibrinogenemia, AMI: Acute myocardial infarction.]
To cite this abstract in AMA style:Rosa CM, Neerman-Arbez M, Duboscq C, Vilaseca A, Ceresetto J, Aris Cancela ME, Colimodio P, Barrera L, Lopez MS, Oyhamburu JM, Privitera V, Viñuales ES, Nucifora E, Kalmus M, Meschengieser S, Casini A, de Moerloose P, Martinuzzo ME. Congenital Qualitative Fibrinogen Disorders: Case Series from Argentina; Multicentric Collaborative Study [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/congenital-qualitative-fibrinogen-disorders-case-series-from-argentina-multicentric-collaborative-study/. Accessed May 6, 2021.
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