Whole Blood Thromboelastometry by ROTEM and Thrombin Generation by Genesia According to the Genotype and Clinical Phenotype in Congenital Fibrinogen Disorders.

Timea Szanto,Marguerite Neerman-Arbez,Alessandro Casini,Marja Lemponen,Elina Lehtinen,Riitta Lassila

doi:10.3390/ijms22052286

Abstract

The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia® with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bβ chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among FGG and FGA mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure–function relationship of fibrin to support hemostasis.

Highlights

Congenital fibrinogen disorders (CFD) are rare disorders affecting either the quantity or the quality or both of fibrinogen (Fg) [1]
We aimed to assess the clinical outcome by studying thrombin generation (TG) by ST Genesia® and ROTEM
Nine patients were diagnosed with hypofibrinogenemia based on concordant Fg activity and antigen levels, with median Fg activity level of 0.8 g/L

Summary

Introduction

Congenital fibrinogen disorders (CFD) are rare disorders affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (dysfibrinogenemia) or both (hypodysfibrinogenemia) of fibrinogen (Fg) [1]. Hypofibrinogenemia and dysfibrinogenemia are the most frequent types of CFD, characterized by decreased levels of both Fg activity and antigen in the former, and discrepant levels of dysfunctional Fg in the latter. They usually result from heterozygous mutations affecting one of the three fibrinogen genes (i.e., FGA, FGB, or FGG) [2]. The diagnosis of most CFD is usually quite straightforward based on standard coagulation assays [6,7], these conventional tests fail to predict the clinical phenotype.

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Methods

Conclusion