Platelet activation in clinical haemodialysis:: LMWH as a major contributor to bio-incompatibility?
Platelet activation in clinical haemodialysis:: LMWH as a major contributor to bio-incompatibility?
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DOI：
10.1093/ndt/gfn137
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发表时间：
2008-09-01
影响因子：
6.1
通讯作者：
Nube, Menso J.
中科院分区：
文献类型：
--
作者：
Gritters, Mareille;Borgdorff, Piet;Nube, Menso J.
背景血液透析（HD）期间发生的不良副作用的总和称为生物不相容性。关于血小板，已经描述了细胞表面标志物P-选择素（CD 62 p）的表达增加和细胞内颗粒产物血小板因子4（PF 4）的释放。然而，由于PF 4也大量存在于内皮结合蛋白聚糖上，因此HD诱导的增加是否完全归因于血小板的释放是值得怀疑的。关于HD引起的生物不相容性的原因，主要关注体外循环回路（ECC），尤其是透析器，而很少关注ECC的其他部分和所应用的抗凝模式。为了解决临床血液透析过程中血小板活化和PF 4释放的原因和起源，进行了两项互补的临床研究。在研究I中，ECC的各个部分的相对影响进行了评估，通过测量的表达CD 62 p，血小板聚集和PF 4和血清素的水平在不同的采样点。在研究II中，低分子量肝素（LMWB）在实际开始HD前10分钟给药，以分离LMWH和ECC对血小板活化的影响。在研究I中，CD 62 p表达在整个ECC长度上增加，包括滚子泵和透析器（15时的中位数从26%增加到43%，P = 0.008; t（30）时的中位数从28%增加到48%，P = 0.007）。PF 4和血小板聚集的增加相对适度。血小板5-羟色胺含量低于健康对照组的参考值，血浆5-羟色胺浓度高于参考值，但没有变化。在研究II中，注射LMWH后PF 4水平显著升高（从t（-10）时的12 IU/ml增加到t（0）时的75 IU/ml，P = 0.018），而CD 62 p表达在HD开始前保持稳定。通过CD 62 p的上调测量的血小板活化是一个早期过程，不仅发生在透析器内，而且发生在整个ECC长度上。由于在HD实际开始前10分钟给予LMWH后CD 62 p保持不变，因此这种激活与LMWH无关。然而，考虑到PF 4，在LMWH给药后和HD开始前观察到急剧增加。这一发现表明，在临床HD早期观察到的PF 4释放在很大程度上独立于ECC，并且可能是LMWH诱导的内皮脱离的结果。由于血小板5-羟色胺含量相对降低，血浆5-羟色胺水平升高，慢性HD患者的血小板可能因慢性重复激活而耗竭。基于这些数据，首先，PF 4是临床HD中血小板活化的劣效标志物，其次，LMWH是HD诱导的生物不相容性的主要促成因素。
Background. The sum of undesirable side effects, occurring during haemodialysis (HD), is called bio-incompatibility. Concerning platelets, both an increase in the expression of the cell surface marker P-selectin (CD62p) and release of the intracellular granule product platelet factor 4 (PF4) have been described. However, as PF4 is also abundantly present on endothelium-bound proteoglycans, it is questionable whether the HD-induced increase is exclusively attributable to release from platelets. With respect to the cause of HD-induced bio-incompatibility, interest has been focused mainly on the extracorporeal circuit (ECC), especially the dialyser, whereas only little attention has been paid to other parts of the ECC and the mode of anticoagulation applied. To address the cause and origin of platelet activation and PF4 release during clinical HD, two complementary clinical studies were performed.Materials and methods. In study I, the relative influence of the various parts of the ECC was evaluated by measuring the expression of CD62p, platelet aggregation and levels of PF4 and serotonin at various sampling points. In study II, low-molecular-weight heparin (LMWB) was administered 10 min before the actual start of HD, in order to separate the effects from LMWH and the ECC on platelet activation.Results. In study I, CD62p expression increased across the entire length of the ECC, including the roller pump and dialyser (median at 15 from 26% to 43%, P = 0.008; median at t(30) from 28% to 48%, P = 0.007). Increments in PF4 and aggregation of platelets were relatively modest. Platelet serotonin content, which was below reference values in healthy controls, and plasma serotonin concentration, which was above reference values, did not change. In study II, PF4 levels increased markedly after the injection of LMWH (from 12 IU/ml at t(-10) to 75 IU/ml at t(0), P = 0.018), whereas CD62p expression remained stable until the start of HD.Conclusions. Platelet activation, as measured by the up-regulation of CD62p, is an early process, occurring not only within the dialyser, but across the entire length of the ECC. As CD62p remained unaltered after the administration of LMWH 10 min before the actual start of HD, this kind of activation is independent of LMWH. Considering PF4 however, a sharp increment was observed after the administration of LMWH and before the start of HD. This finding suggests that the PF4 release observed early in clinical HD is largely independent from the ECC, and is probably the result of LMWH-induced detachment from the endothelium. As the platelet serotonin content was relatively reduced and the plasma serotonin levels were elevated, platelets from chronic HD patients might be depleted due to chronic repetitive activation. Based on these data, it appears first, that PF4 is an inferior marker of platelet activation in clinical HD and second, that LMWH is a major contributor to HD-induced bio-incompatibility.