Response: Elevated fibrinogen γ′ ratios and clinical outcomes

In a candidate gene approach we recently have investigated the association between fibrinogen α (FGA) and fibrinogen γ (FGG) haplotypes, the factor V^Leiden mutation, and pediatric venous thrombosis (VT) and thromboembolic stroke (TS) in 2 independent study samples. In addition, we examined the association between genetic variation in FGG and FGA genes and plasma levels of γA/γ′ fibrinogen in the group of VT children.¹  We found in an independent study sample that FGA-H1 and FGG-H2 were significantly associated with TS and, furthermore, that the association of FGA and FGG haplotypes with VT was more pronounced in FV^Leiden-negatives, indicating a genetic interaction between both risk factors. In the subgroup analysis (VT) the risk-conferring FGG-H2 and the protective FGG-H3 haplotypes correlated with low (FGG-H2) and high (FGG-H3) levels of the γ′ chain variant. Our results have provided independent and novel evidence that (1) FGA-H1 and FGG-H2 variants are associated with an increased risk of VT and TS in children, and (2) the observed negative correlation of genetic VT risk with the plasma levels of the fibrinogen γ′ variant suggests that FGG-H2 and -H3 haplotypes modify thrombosis risk by controlling the level of this FGG splice isoform.

In response to our manuscript, Cheung and coworkers note that elevated fibrinogen γ′ ratios are associated with cardiovascular diseases and acute phase reaction but not with clinical outcome. This is an interesting observation regarding the use of γ′ levels/ratios as a predictive biomarker for short-term clinical course. The authors tentatively explain this observation with altered mRNA processing of the fibrinogen γ′ during an acute phase reaction. The data by Cheung and colleagues, however, should not be intermingled with the genetic issues that are subject of our publication.¹  As pointed out correctly by Cheung et al, in our cohort study blood samples for fibrinogen γ′ investigation clearly have been drawn beyond the acute phase, 6 to 12 months after acute VT onset. Thus, on the bases that (1) none of the children investigated by us had evidence of acute phase reactions (underlined by normal values of high sensitive C-reactive protein, von Willebrand factor antigen [data not shown]), (2) missing nonacute fibrinogen γ′ levels, and (3) missing fibrinogen haplotype associations in the cohort by Cheung and coworkers, both scientific reports cannot be directly compared. Whether fibrinogen γ′ serves as a predictive biomarker for acute phase reaction, for short- or long-term clinical outcomes or both, should be addressed in future prospective studies.