Protein N-linked homocysteine is associated with recurrence of venous thromboembolism

Recently, protein N-linked homocysteine (Hcy) has been measured in healthy subjects and patients with marked hyperhomocysteinemia. Since elevated total Hcy (tHcy) levels are associated with increased risk of venous thromboembolism (VTE), we aimed to investigate protein N-linked Hcy levels in patients with VTE.

We studied 200 consecutive patients with VTE (89 men, 111 women, aged from 17 to 83 years), including 57 subjects with a subsequent episode of VTE (recurrent VTE) during 24 months of follow-up. Protein N-linked Hcy was assayed using high-performance liquid chromatography with an on-column derivatization with o-phthaldialdehyde and fluorescence detection.

The median protein N-linked Hcy was 1.404 μM (interquartile range [IQR] 0.859-2.066), while the median tHcy (IQR) was 9.1 μM (6.8-11.2). In the whole group protein N-linked Hcy correlated only with C-reactive protein (CRP; r = 0.44, p < 0.0001). In patients with recurrent VTE protein N-linked Hcy correlated with C-reactive protein (r = 0.43, p < 0.0001), tHcy (r = 0.42, p = 0.001) and age (r = 0.32, p = 0.014), but not with thrombophilia, unprovoked VTE or the current anticoagulation. Hyperhomocysteinemia, defined as tHcy ≥ 15 μM (n = 14.7%), was not associated with higher protein N-linked Hcy. Patients with recurrent VTE had higher levels of protein N-linked Hcy compared to those who experienced a single episode of VTE (1.553 μM, 1.157-2.445 vs. 1.27 μM, 0.826-1.884; p = 0.002). Multiple regression adjusted for potential confounders showed that the only independent predictor of protein N-linked Hcy in the upper quartile was CRP > 3mg/L (odds ratio 3.04, 95% confidence interval 2.12-4.36, p < 0.0001).

Elevated protein N-linked Hcy concentrations, indicating enhanced protein homocysteinylation in vivo, characterize patients with recurrent VTE and this phenomenon is associated with enhanced inflammatory state.