Introduction Directory UMM :Data Elmu:jurnal:A:Atherosclerosis:Vol154.Issue1.Jan2001:

Atherosclerosis 154 2001 203 – 212 Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients Eriko Morishita a,b, , Hidesaku Asakura b , Masanori Saito b , Masahide Yamazaki b , Yasuo Ontachi b , Tomoe Mizutani b , Minori Kato b , Tamotsu Matsuda b , Shinji Nakao b a Department of Laboratory Sciences, School of Health Science, Kanazawa Uni6ersity, 13 - 1 Takaramachi, Kanazawa 920 - 8641 , Japan b Department of Internal Medicine III , School of Medicine, Kanazawa Uni6ersity, 13 - 1 Takaramachi, Kanazawa 920 - 8641 , Japan Received 4 June 1999; received in revised form 25 February 2000; accepted 2 March 2000 Abstract Several studies have previously reported high levels of total tissue factor pathway inhibitor TFPI antigen in patients with hypercholesterolemia. The relationship between serum lipid concentrations and total and free-form TFPI antigen in 32 patients with primary type II hypercholesterolemia and 38 age- and gender-matched normolipemic control subjects was studied Study Group I. Plasma concentrations of total TFPI tTFPI antigen, free-form TFPI fTFPI antigen, tissue factor antigen, factor VII activity FVIIc, and prothrombin fragment 1 + 2 F1 + 2 were measured. The median levels of tTFPI, fTFPI, FVIIc, and F1 + 2 were higher in hyperlipidemic patients compared with those in healthy subjects. The effect of lowering total cholesterol on hypercoagulability in 25 patients with type II hyperlipoproteinemia Study Group II were also studied. The median levels of tTFPI, FVIIc, and F1 + 2 decreased significantly after 6 months of 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase inhibitor therapy in the hypercholesterolemic patients. On the other hand, fTFPI did not change after therapy. Plasma tTFPI was strongly correlated with total cholesterol and low density lipoprotein LDL-cholesterol in hyperlipidemic patients. In contrast to the strong correlation between tTFPI and total cholesterol, the correlation between plasma fTFPI and total cholesterol was relatively poor. These results suggest that the activation of the anticoagulant system as well as the activation of the coagulation system may occur in association with hypercholesterolemia. Furthermore, the results of this study may suggest that lowering of total cholesterol in hyperlipidemic patients reduces the thrombin generation in plasma and that down-regulation of LDL does not affect the anticoagulant potency of TFPI in plasma. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords : Tissue factor pathway inhibitor; Hypercoagulability; Hypercholesterolemia; Anticoagulant; HMG-CoA reductase inhibitor www.elsevier.comlocateatherosclerosis

1. Introduction

Tissue factor pathway inhibitor TFPI is a vascular anticoagulant which inhibits the initial reaction of the tissue factor-mediated coagulation pathway [1,2]. TFPI is synthesized mainly by vascular endothelial cells [3] and is associated with these cells [4,5]. In plasma, TFPI can be separated by gel filtration into a free-form and low density lipoproteinvery low density lipoprotein LDLVLDL-associated form and a high density lipo- protein HDL-associated form. The levels of the free- form TFPI fTFPI may be important, since the endothelial cell-associated forms of TFPI is released as the free form by both heparin injection [4,5] and patho- logical stimuli [6]. Recently it has become possible to measure plasma concentrations of total TFPI tTFPI free-form and lipoprotein-associated forms [7] and fTFPI [8]. Then the levels of plasma tTFPI and plasma fTFPI have been demonstrated to vary in several pathophysiologic conditions [9 – 14]. The method for measuring free-form TFPI antigen can be used for assessing changes in the levels of endothelial cell-associ- ated TFPI antigen, which can be released by heparin injection [9]. Total plasma TFPI correlates significantly with plasma total cholesterol and LDL cholesterol lev- els both in normal subjects [13] and in hypercholes- Corresponding author. Tel.: + 81-762-658151; fax: + 81-762- 344252. E-mail address : erikomed3.m.kanazawa-u.ac.jp E. Morishita. 0021-915001 - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0021-91500000463-9 terolemic patients [14]. It is elucidated that the antico- agulant activity of lipoprotein-associated TFPI is markedly lower than that of fTFPI [15]. Therefore, fTFPI antigen was analyzed in plasma in hyperlipi- demic patients and the relation between fTFPI and lipoproteins was further investigated. Moreover, it is also elucidated that TFPI activity and total TFPI antigen normalize during cholesterol-lower- ing therapy because of a specific drop in LDL-associ- ated TFPI in plasma [16]. Almus et al. have found that reducing plasma TFPI by 50 causes a similar increase in the factor VIIa-TF catalytic activity toward factor IX in an umbilical vein model of coagulation [17]. The question then arises whether the changes observed in tTFPI concentrations after cholesterol-lowering therapy should be considered beneficial or not. Therefore, in the present study, some parameters of the hemostatic sys- tem were monitored in order to determine whether decreases in tTFPI induced by cholesterol-lowering therapy reduce the anticoagulant potency of plasma in hyperlipidemic patients.

2. Subjects and methods