Department of Pediatrics, Critical Care Section, Baylor College of Medicine, Houston, TX, USA.
Thromb Res. 2013 Jul;132(1):69-76. doi: 10.1016/j.thromres.2013.04.018. Epub 2013 May 11.
Histones are small, nuclear proteins that serve to package DNA. Recent reports suggest that extracellular histones, including histone H4, may contribute to the pathogenesis of sepsis; they promote platelet aggregation and thrombosis when released into the circulation during inflammation or cell death. The mechanisms by which the body minimizes the deleterious effects of circulating histones are unclear. Because histones can bind to plasma proteins, including albumin, we hypothesized that normal albumin can prevent histones from activating platelets.
Platelets and platelet-free plasma were obtained from healthy, adult subjects. The dose-dependent effects of histone H4 on platelet aggregation were studied by optical aggregometry. The effects of native and albumin-depleted plasma (prepared by affinity chromatography) on histone-induced platelet aggregation were also assessed. The effects of normal and surface-neutralized albumin (through modification of carboxyl groups) on histone-induced platelet activation and aggregation were evaluated using flow cytometry and aggregometry.
Histone H4 induced platelet aggregation in a dose-dependent manner. This histone-induced platelet aggregation was inhibited by both plasma and human serum albumin in a dose-dependent fashion. Furthermore, depletion of albumin from plasma reduced its ability to inhibit aggregation. Finally, surface neutralization of albumin decreased its ability to inhibit histone-induced activation and aggregation.
These data suggest that normal albumin serves a role in preventing histone-induced platelet aggregation in a charge-dependent manner.
组蛋白是一种小型核蛋白，可用于包装 DNA。最近的报告表明，细胞外组蛋白，包括组蛋白 H4，可能有助于脓毒症的发病机制；当炎症或细胞死亡导致组蛋白释放到循环中时，它们会促进血小板聚集和血栓形成。目前尚不清楚身体通过何种机制将循环组蛋白的有害作用降至最低。由于组蛋白可以与包括白蛋白在内的血浆蛋白结合，我们假设正常的白蛋白可以防止组蛋白激活血小板。
从健康的成年受试者中获得血小板和无血小板血浆。通过光学聚集仪研究组蛋白 H4 对血小板聚集的剂量依赖性影响。还评估了天然和白蛋白耗尽的血浆（通过亲和层析制备）对组蛋白诱导的血小板聚集的影响。使用流式细胞术和聚集仪评估正常和表面中和白蛋白（通过修饰羧基）对组蛋白诱导的血小板激活和聚集的影响。
组蛋白 H4 以剂量依赖性方式诱导血小板聚集。这种组蛋白诱导的血小板聚集可被血浆和人血清白蛋白以剂量依赖性方式抑制。此外，从血浆中耗尽白蛋白会降低其抑制聚集的能力。最后，白蛋白表面中和降低了其抑制组蛋白诱导的激活和聚集的能力。
这些数据表明，正常的白蛋白以电荷依赖的方式在阻止组蛋白诱导的血小板聚集中发挥作用。
