Elevated fibrinogen γ′ ratio is associated with cardiovascular diseases and acute phase reaction but not with clinical outcome

To the editor:

Recently, Nowak-Göttl et al reported on the association between the fibrinogen γ′/total fibrinogen ratio (γ′ ratio) and thromboembolism in children.¹  We and others previously reported on this association in adults.^2-6  However, the underlying mechanism remains unknown. Recently, we reported that the γ′ ratio is higher in the acute phase of ischemic stroke (IS), but not in the convalescent phase.²  This suggests that the acute phase reaction alters the mRNA processing of fibrinogen γ, thereby increasing the γ′ ratio. Furthermore, the anti- and prothrombotic properties of γ′-fibrinogen suggest that an increased γ′ ratio during the acute phase of cardiovascular disease may influence the secondary thrombotic risk.

Fibrinogen γ′ antigen levels were measured by enzyme-linked immunosorbent assay as described previously.⁴  Total fibrinogen levels were measured according to von Clauss, and C-reactive protein (CRP) levels were measured using an in-house high-sensitivity enzyme-linked immunosorbent assay. Statistical analysis was performed using SPSS 16.0 for Windows. All investigations were approved by the Medical Ethics Committee of Erasmus University Medical Center and were performed in accordance with the recommendations of the Declaration of Helsinki.

We confirmed our previous finding of an elevated γ′ ratio in IS and observed significantly higher γ′ ratios in the acute phase of IS (independent cohort of 53 patients), pulmonary embolism (PE, n = 29)⁷  and unstable angina pectoris (UAP, n = 202)⁸  compared with the γ′ ratios in healthy controls (P < .001; Table 1). These observations are in contrast to those of Nowak-Göttl et al, who reported a decreased γ′ ratio in children with thromboembolism (U. Nowak-Göttl, H. Weiler, personal communication, July 2009),¹  and also with results from adult patients with deep venous thrombosis.⁴  One explanation for the discrepancy may be the timing of blood collection. In our studies, blood was collected in the acute phase of the diseases. We observed a significant correlation between γ′ ratios and CRP levels in the acute phase (Rs = 0.23, P < .001) in the patients with IS.²  Moreover, γ′ ratios were slightly higher (0.24 ± 0.19, n = 16) in PE patients with CRP levels > 100 mg/L, than in patients who did not have an acute phase response (CRP levels ≤ 10 mg/L; 0.20 ± 0.06, n = 13, P = .54). These results together support our hypothesis that the mRNA processing of the fibrinogen γ alters during an acute phase reaction.

The characteristics of γ′-fibrinogen suggest that a high ratio during the acute phase of disease prevents thrombotic events in patients with UAP. In our patient group, there was no difference in ratios between stabilized (n = 130) and refractory (n = 72) patients (both 0.14 ± 0.04, P = .59). Neither were the ratios associated with clinical outcome during 18 months of follow-up. These results suggest that elevated ratio does not predict the risk of acute coronary syndromes in patients with UAP.

In conclusion, the fibrinogen γ′/total fibrinogen ratios are elevated in patients with various cardiovascular diseases (IS, PE, or UAP) compared with the γ′ ratios in healthy controls. An altered mRNA processing of fibrinogen γ during the acute phase may contribute to this observation. However, the fibrinogen γ′/total fibrinogen ratio does not predict short- or long-term outcome in patients with UAP.