Unit of Autoimmunity and Vascular Inflammation, Division of Regenerative Medicine, Gene Therapy and Stem Cells, Istituto Scientifico San Raffaele and Universita Vita-Salute San Raffaele, Milan, Italy.
Blood. 2011 Sep 22;118(12):3359-66. doi: 10.1182/blood-2011-02-337337. Epub 2011 Jun 24.
Essential thrombocythemia (ET) and polycythemia vera (PV) are characterized by persistent platelet activation. The mechanisms involved in their clearance are poorly characterized. In the present study, we report that leukocytes were actively involved in platelet disposal in 51 patients with ET and 30 with PV, but not in 70 age- and sex-matched controls. The fraction of circulating neutrophils and monocytes that had phagocytosed platelets, as assessed by flow cytometry, was significantly higher in patients with PV or ET, independently of hydroxyurea treatment, than in controls. Platelet phagocytosis by circulating leukocytes was confirmed by confocal and electron microscopy. The lack of effect of hydroxyurea, which disrupts the P-selectin/P-selectin glycoprotein ligand 1 (PSGL-1) interaction, suggests a P-selectin-independent mechanism. This hypothesis was confirmed in an ad hoc animal model based on the in vivo injection of activated platelets from P-selectin(+/+) and P-selectin(-/-) mice. P-selectin expression was associated with an earlier and effective clearance of platelets by neutrophils. A second delayed, P-selectin-independent phase actively involved monocytes. Our results suggest that phagocytic clearance of platelets by leukocytes occurs in PV and ET, possibly involving P-selectin-dependent and -independent pathways, thus representing a novel mechanism to remove activated platelets from the circulation.
特发性血小板增多症 (ET) 和真性红细胞增多症 (PV) 的特征是血小板持续活化。其清除机制尚未完全阐明。本研究报告称，在 51 例 ET 患者和 30 例 PV 患者中，白细胞积极参与了血小板的清除，但在 70 名年龄和性别匹配的对照者中没有这种现象。通过流式细胞术评估，循环中性粒细胞和单核细胞中吞噬血小板的比例在 PV 或 ET 患者中明显高于对照组，且与羟基脲治疗无关。通过共聚焦和电子显微镜确认了循环白细胞对血小板的吞噬作用。由于羟基脲会破坏 P-选择素/P-选择素糖蛋白配体 1 (PSGL-1) 的相互作用，因此不会影响血小板的吞噬作用，这表明存在一种 P-选择素非依赖性机制。在基于从 P-选择素(+/+)和 P-选择素(-/-)小鼠体内注射激活血小板的专门动物模型中证实了这一假设。P-选择素的表达与中性粒细胞更早、更有效的血小板清除有关。第二个延迟的、P-选择素非依赖性阶段则积极涉及单核细胞。我们的研究结果表明，白细胞通过吞噬作用清除血小板发生在 PV 和 ET 中，可能涉及 P-选择素依赖性和非依赖性途径，因此代表了一种从循环中清除活化血小板的新机制。
