van Hinsbergh V W, Bauer K A, Kooistra T, Kluft C, Dooijewaard G, Sherman M L, Nieuwenhuizen W
Gaubius Institute TNO, Leiden, The Netherlands.
Blood. 1990 Dec 1;76(11):2284-9.
Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI-1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion, whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were slightly decreased, 5% on average, suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products, and separately of fibrin degradation products and fibrinogen degradation products, was found. This indicates that fibrinolysis persisted, at least partly, in the presence of high levels of PAI activity. Whereas PAI-1 production increased, t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore, it is possible that thrombin, not TNF, is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients.
几位研究者报告称，肿瘤坏死因子（TNF）在体外可改变内皮细胞纤溶酶原激活物1型（PAI-1）和纤溶酶原激活物（PAs）的生成。我们通过对17例患有活动性疾病的癌症患者连续输注TNF 24小时期间血浆中的参数评估，研究了重组人TNF给药对体内纤溶的影响。TNF输注3小时和24小时后，PAI活性的血浆水平增加了7倍。这是PAI-1抗原增加的结果；未检测到PAI-2抗原。TNF输注3小时和24小时后，组织型PA（t-PA）抗原的血浆浓度增加了2至5倍，而血浆中尿激酶型PA抗原水平保持不变。TNF输注3小时后，α2-抗纤溶酶的血浆水平略有下降，平均下降5%，提示纤溶仍在继续。TNF输注24小时后，发现纤维蛋白加纤维蛋白原降解产物以及单独的纤维蛋白降解产物和纤维蛋白原降解产物均显著增加。这表明在PAI活性水平较高的情况下，纤溶至少部分持续存在。虽然PAI-1生成增加，但体外人内皮细胞在添加TNF时t-PA生成保持不变甚至减少。先前已表明，在我们的患者中输注TNF会导致凝血酶和纤维蛋白生成。因此，有可能凝血酶而非TNF是我们患者中t-PA生成的实际刺激因素。我们推测在TNF输注期间形成了纤维蛋白，并且纤溶酶是由t-PA作用于（可溶性）纤维蛋白分子的初始形成而立即产生的。这样一个过程可能解释了在患者输注TNF期间纤维蛋白和纤维蛋白原降解产物的生成。
