Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial

Introduction: Cigarette smoking may induce Pro-inflammatory and pro-thrombotic changes. It is not known whether these abnormalities are caused at least partly by increased homocysteine levels. We investigated whether lowering homocysteine by folic acid supplementation might reduce the plasma concentration of inflammatory and thrombogenic markers in chronic smokers. Material and methods: Twenty-four healthy cigarette smokers (age 37.8 +/- 2.5 years, mean +/- SEM) were randomly assigned to 4 weeks of folic acid 5 mg/day or placebo. The following parameters were measured before and after treatment: (1) markers of inflammation (C-reactive protein, CRP, and white cell count, WCC); (2) blood coagulation screen (Activated Partial Thromboplastin time Ratio, APTR, and International Normalized Ratio, INR); (3) pro-thrombotic markers (fibrinogen, factor VIII coagulant activity, VIII:C, von Willebrand factor, vWF, and D-dimer). Results: Folic acid induced a significant reduction in homocysteine (10.8 +/- 0.6 vs. 8.2 +/- 0.5 mumol/l, p < 0.001), plasma fibrinogen (3.15 +/- 0.14 vs. 2.87 +/- 0.14 g/l, p < 0.05), and D-dimer (102 +/- 44 vs. 80 +/- 26 mug/l, p < 0.05) concentrations. By contrast, no significant changes were observed in CRP (2.2 +/- 0.7 vs. 1.7 +/- 0.7 mg/l), WCC (7.2 +/- 0.5 vs. 6.8 +/- 0.5 10(9) cells/l), APTR (0.91 +/- 0.02 vs. 0.93 +/- 0.02), INR (0.92 +/- 0.01 vs. 0.91 +/- 0.01), vWF (103 +/- 8 vs. 102 +/- 9 U/dl), and VIII:C (120 +/- 8 vs. 107 +/- 8 U/dl) levels. Changes in folic acid plasma concentrations were significantly and negatively correlated with changes in fibrinogen (r = - 0.48, p = 0.01) but not with changes in D-dimer (r = -0.15, p = 0.5) levels. Changes in plasma homocysteine concentrations did not correlate with changes in either fibrinogen or D-dimer. No significant changes in homocysteine, inflammatory and thrombogenic markers were observed in the placebo group. Conclusions: Short-term folic acid supplementation had no significant effects on inflammatory markers but induced a significant reduction in plasma fibrinogen and D-dimer concentrations in healthy chronic smokers. Thus, folic acid might have an anti-thrombotic effect in this high-risk group independent of the homocysteine lowering effect. (C) 2003 Elsevier Ltd. All rights reserved.