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

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.

Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management

“…This study has limitations for a low number of cohorts. Further large, multicenter studies are needed to confirm these data [75].…”

“…Substitution therapy is effective in the treatment of bleeding episodes in congenital fibrinogen disorders [55,75]. If possible, specific plasma-derived factor concentrate deprived of active viruses ought to be administered preferentially in rare bleeding diseases.…”

“…Fresh frozen plasma (FFP) or cryoprecipitate should be administered in the unavailability of plasma-derived factor concentrate [3]. FFP has several disadvantages: the decreased amount of fibrinogen that is infused leads to the need to repeat the administration more times to achieve the appropriate fibrinogen level; in addition, there are transfusion-related risks (e.g., transfusion-related acute lung injury (TRALI) and transmission of virus infections) [75,76]. In addition, cryoprecipitate has many of these handicaps; it also needs compatibility testing, thawing, and it has a complicated application [76].…”

Dysfibrinogenemia—Potential Impact of Genotype on Thrombosis or Bleeding

“…One of four Chinese cases presented bleeding symptoms, 36 while three were asymptomatic. Two Italian cases and a Swiss case recently reported by Castaman et al 25 and by Szanto et al 35 were asymptomatic. Moreover, in seven cases with other amino acid substitutions at Arg19, two patients with an Arg19Ser mutation, 15,31,33 one patient with the Arg19Asn mutation, 34 one Iranian patient with the Arg19Thr mutation, 30 and one Chinese patient with Arg19Trp mutation 23 bleeding or bleeding tendency were common clinical symptoms.…”

“…Five different mutations have been reported at the Arg19 position (►Table 4). Most frequent is the Arg!Gly mutation, which has been identified in 12 studies including the present study 13,[18][19][20][21][24][25][26][27][28][29]32,35,36 (►Tables 1 and 4). The four other mutations encompass Arg!Ser, 15,31,33 Arg!Asn, 34 Arg!Thr, 22,30 and Arg!Trp.…”