40. Modulation of plasma fibrinogen levels by ticlopidine in healthy volunteers and patients with stable angina pectoris

Abstract

Elevated plasma fibrinogen levels represent an increased risk for cardiac events. Ticlopidine is a drug that inhibits the ADP-induced aggregation of blood platelets and it also has been described that ticlopidine can decrease the plasma fibrinogen level in patients with vascular diseases. The mechanism of this decrease has not yet been elucidated and therefore mechanisms that are known to affect fibrinogen levels were studied, viz. the acute phase reaction, total fibrin and fibrinogen degradation (TDP) levels and the fibrinogen G/A4 -gene polymorphism. The fibrinogen lowering effect of ticlopidine was studied in 26 healthy volunteers and in 26 patients with stable angina pectoris in a double blind, randomized cross-over study versus placebo. Functional plasma fibrinogen levels were measured with the Clauss assay and antigen levels with an enzyme immunoassay. C-reactive protein (CRP) and TOP levels were measured with an enzyme immuno assay. In the healthy volunteers the mean (SD) baseline level of functional plasma fibrinogen was 2.35 g/L (SD 0.35) and for fibrinogen antigen this was 2.49 g/L (SD 0.63). The geometrical mean (central 95% range) of CRP as 0.21 mg/L (0.02-2.36) and for TOP this was 0.18 ng/mL (0.03-1.00). After 4 weeks of ticlopidine administration, the functional fibrinogen levels had decreased with 0.20 g/L (9%, p=0.005 using the paired Student t-test) whereas the fibrinogen antigen levels, the CRP and the TOP levels had not significantly changed. In the stable angina pectoris patient the mean (SD) baseline levels of functional plasma fibrinogen were 3.44 g/L (SD 0.61) and of fibrinogen antigen they were 2.60 g/L (SD 0.49). The geometrical mean (central 95% range) of CRP was 1.45 mg/L (0.15-14.44) and for TOP this was 0.28 ng/mL (0.05-1.62). These baseline fibrinogen, CRP and TOP levels were significantly higher than in the volunteer group. After four weeks ticlopidine administration the functional fibrinogen levels had decreased with 0.39 g/L (11%, p<0.005), whereas the fibrinogen antigen, the CRP and the TDP levels had not significantly changed. The functional and antigen levels of fibrinogen, CRP and TDP did not change significantly during the placebo period in the volunteers or the patients. Neither in the volunteers nor in the patients was the effect of ticlopidine on the fibrinogen levels associated with the fibrinogen G/A~455 genotype. Therefore, the fibrinogen lowering effect of ticlopidine is likely to be a modulation of the functionality of the molecule and unlikely to be modulated by the acute phase reaction, TDP-levels or the fibrinogen β-gene polymorphisms. © Pearson Professional Ltd 1996.