Kockx M, de Maat M P, Knipscheer H C, Kastelein J J, Kluft C, Princen H M, Kooistra T
Gaubius Laboratory, TNO-PG, Leiden, The Netherlands.
Thromb Haemost. 1997 Oct;78(4):1167-72.
Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6% (p <0.05) and 24.3% (p <0.001) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2% (p <0.05) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5% (p <0.0001) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1% (p <0.001) and 10.5% (p <0.0001), respectively on the basis of Clauss mechanical and by 14.2% (p <0.001) and 28.2% (p <0.0001), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen (determined by either of the two Clauss assays) to fibrinogen antigen. Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and/or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen.
在人体中对贝特类药物治疗的评估主要集中在其抗血脂作用上。贝特类药物潜在的有利的止血调节活性也已得到认可，但数据并不一致。我们试图通过使用不同的PAI-1和纤维蛋白原检测系统，研究吉非贝齐和环丙贝特对原发性高脂血症患者治疗6周和12周后血浆组织型纤溶酶原激活物（t-PA）、纤溶酶原激活物抑制剂-1（PAI-1）和纤维蛋白原水平的影响，以更多地了解这种变异性。尽管两种贝特类药物均有效降低了甘油三酯和胆固醇水平，但在贝特类药物治疗后，未观察到对升高的t-PA和PAI-1基线抗原水平有影响。然而，两种贝特类药物均以不同方式影响血浆纤维蛋白原水平。吉非贝齐治疗6周和12周后，纤维蛋白原抗原水平分别升高了17.6%（p<0.05）和24.3%（p<0.001），而环丙贝特则无影响。使用具有机械终点或基于比浊终点的Clauss功能测定法，吉非贝齐治疗6周后纤维蛋白原水平未见显著变化。然而，12周后，根据Clauss机械测定法，吉非贝齐使功能性纤维蛋白原水平提高了7.2%（p<0.05），但使用基于比浊的Clauss测定法时，功能性纤维蛋白原水平降低了12.5%（p<0.0001）。环丙贝特治疗6周或12周后，基于Clauss机械测定法，功能性纤维蛋白原水平分别降低了10.1%（p<0.001）和10.5%（p<0.0001），使用Clauss比浊测定法时分别降低了14.2%（p<0.001）和28.2%（p<0.0001）。两种贝特类药物一个显著且一致的发现是，通过功能性纤维蛋白原（由两种Clauss测定法中的任何一种测定）与纤维蛋白原抗原的比值评估，纤维蛋白原的功能降低。综上所述，我们的结果表明，贝特类药物对止血参数影响的变异性至少部分可以通过不同贝特类药物之间的内在差异、治疗时间的差异和/或各种检测系统的不同结果来解释。有趣的是，所测试的两种贝特类药物均降低了纤维蛋白原的功能。
