title: Protein C pathway impairment in nonsymptomatic cigarette smokers.
abstract: Increased risk of thrombosis in cigarette smokers implies the existence of an underlying prethrombotic state. It is known that oxidative damage to the endothelium surface occurs in chronic smokers. Protein C activation takes place mostly on the endothelium of small vessels and the anticoagulant activity of protein C requires the presence of lipid membranes that are vulnerable to oxidation. Our objective was to analyze the relationship between smoking and plasma levels of activated protein C, protein C zymogen, activated protein C complexed with serpins, total and free protein S, C4b-binding protein, and thrombomodulin, as well as fibrinogen, fibrinopeptide A, and protease-cleaved antithrombin III. Of the 189 plasma donors used in this study 83 were nonsymptomatic smokers (age range 20-44 years, women/men ratio = 1.13) and 106 were healthy nonsmokers (age range 22-59 years, women/men ratio = 1.36). Smokers had 23.3% lower circulating activated protein C than nonsmokers (p = 0.003) and the differences were more pronounced in males than in females. Protein C levels were also significantly lower in smokers than in nonsmokers (p = 0.034). Correlations were negative between the intensity of smoking and circulating activated protein C levels (r = -0.31, p = 0.004) and between smoking and the ratio of activated protein C to protein C zymogen (r = -0.37, p = 0.001). Positive correlations were found between smoking intensity and fibrinogen (r = 0.21, p = 0.042), or fibrinopeptide A (r = 0.219, p = 0.034). Other parameters tested did not show a statistically significant dose-response for the number of cigarettes smoked. Cigarette smoke dose-dependent hypercoagulability due to acquired activated protein C deficiency could contribute to the increased risk of thrombosis in smokers.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road MEM-180, La Jolla, CA 92037, USA. jfernand@scripps.edu
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Heeb
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
mesh_terms: D000328:Adult; D003169:Complement Inactivator Proteins / Q000032:analysis; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005344:Fibrinopeptide A / Q000032:analysis; D006023:Glycoproteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000032:analysis / Q000378:metabolism*; D015843:Serpins / Q000097:blood; D012907:Smoking / Q000009:adverse effects / Q000097:blood*; D018180:Thrombomodulin / Q000097:blood; D019851:Thrombophilia / Q000209:etiology*
chemical_list: D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D011486:Protein C; D015843:Serpins; D018180:Thrombomodulin; D005344:Fibrinopeptide A; D005340:Fibrinogen