Larocca Luigi M, Heller Paula G, Podda Gianmarco, Pujol-Moix Nuria, Glembotsky Ana C, Pecci Alessandro, Alberelli Maria Adele, Balduini Carlo L, Landolfi Raffaele, Cattaneo Marco, De Candia Erica
a Department of Pathology , Policlinico A. Gemelli, Università Cattolica del Sacro Cuore , Rome , Italy .
b Department of Hematology Research , Instituto de Investigaciones Médicas Alfredo Lanari, University of Buenos Aires, CONICET , Buenos Aires , Argentina .
Platelets. 2015;26(8):751-7. doi: 10.3109/09537104.2014.994093. Epub 2015 Mar 25.
The gray platelet syndrome (GPS) is a rare congenital platelet disorder characterized by mild to moderate bleeding diathesis, macrothrombocytopenia and lack of azurophilic α-granules in platelets. Some platelet and megakaryocyte (MK) abnormalities have been described, but confirmative studies of the defects in larger patient cohorts have not been undertaken. We studied platelet function and bone marrow (BM) features in five GPS patients with NBEAL2 autosomal recessive mutations from four unrelated families. In 3/3 patients, we observed a defect in platelet responses to protease-activated receptor (PAR)1-activating peptide as the most consistent finding, either isolated or combined to defective responses to other agonists. A reduction of PAR1 receptors with normal expression of major glycoproteins on the platelet surface was also found. Thrombin-induced fibrinogen binding to platelets was severely impaired in 2/2 patients. In 4/4 patients, the BM biopsy showed fibrosis (grade 2-3) and extensive emperipolesis, with many (36-65%) MKs containing 2-4 leukocytes engulfed within the cytoplasm. Reduced immunolabeling for platelet factor 4 together with normal immunolabeling for CD63 in MKs of two patients demonstrated that GPS MKs display an alpha granule-specific defect. Increased immunolabeling for P-selectin and decreased immunolabeling for PAR1, PAR4 and c-MPL were also observed in MKs of two patients. Marked emperipolesis, specific defect of MK alpha-granule content and defect of PAR1-mediated platelet responses are present in all GPS patients that we could study in detail. These results help to further characterize the disease.
灰色血小板综合征（GPS）是一种罕见的先天性血小板疾病，其特征为轻度至中度出血倾向、大血小板减少以及血小板中缺乏嗜天青α颗粒。虽然已经描述了一些血小板和巨核细胞（MK）异常情况，但尚未对更大患者队列中的缺陷进行确证性研究。我们研究了来自四个无关家庭的五名携带NBEAL2常染色体隐性突变的GPS患者的血小板功能和骨髓（BM）特征。在3/3的患者中，我们观察到血小板对蛋白酶激活受体（PAR）1激活肽的反应存在缺陷，这是最一致的发现，该缺陷可单独出现或与对其他激动剂的反应缺陷合并存在。还发现血小板表面主要糖蛋白表达正常的情况下PAR1受体减少。在2/2的患者中，凝血酶诱导的纤维蛋白原与血小板的结合严重受损。在4/4的患者中，骨髓活检显示纤维化（2 - 3级）和广泛的血细胞吞噬现象，许多（36 - 65%）巨核细胞的细胞质内吞噬有2 - 4个白细胞。两名患者的巨核细胞中血小板因子4的免疫标记减少，而CD63的免疫标记正常，这表明GPS巨核细胞存在α颗粒特异性缺陷。在两名患者的巨核细胞中还观察到P选择素的免疫标记增加，而PAR1、PAR4和c - MPL的免疫标记减少。在我们能够详细研究的所有GPS患者中均存在明显的血细胞吞噬现象、巨核细胞α颗粒内容物的特异性缺陷以及PAR1介导的血小板反应缺陷。这些结果有助于进一步明确该疾病的特征。
