Freie Universität Berlin, Dept. Biochemistry, Germany.
Haematologica. 2012 Jan;97(1):73-81. doi: 10.3324/haematol.2011.049619. Epub 2011 Sep 20.
Thrombocytopenia with absent radii syndrome is defined by bilateral radius aplasia and thrombocytopenia. Due to impaired thrombopoietin signaling there are only few bone marrow megakaryocytes and these are immature; the resulting platelet production defect improves somewhat over time. A microdeletion on chromosome 1q21 is present in all patients but is not sufficient to form thrombocytopenia with absent radii syndrome. We aimed to refine the signaling defect in this syndrome.
We report an extended study of 23 pediatric and adult patients suffering from thrombocytopenia with absent radii syndrome in order to scrutinize thrombopoietin signal transduction by immunoblotting and gel electrophoretic shift assays. In addition, platelet immunotyping and reactivity were analyzed by flow cytometry. Results were correlated with clinical data including age and platelet counts.
Two distinct signaling patterns were identified. Juvenile patients showed abrogated thrombopoietin signaling (pattern #1), which is restored in adults (pattern #2). Phosphorylated Jak2 was indicative of activation of STAT1, 3 and 5, Tyk2, ERK, and Akt, showing its pivotal role in distinct thrombopoietin-dependent pathways. Jak2 cDNA was not mutated and the thrombopoietin receptor was present on platelets. All platelets of patients expressed normal levels of CD41/61, CD49b, and CD49f receptors, while CD42a/b and CD29 were slightly reduced and the fibronectin receptor CD49e markedly reduced. Lysosomal granule release in response to thrombin receptor activating peptide was diminished.
We show a combined defect of platelet production and function in thrombocytopenia with absent radii syndrome. The rise in platelets that most patients have during the first years of life preceded the restored thrombopoietin signaling detected at a much later age, implying that these events are uncoupled and that an unknown factor mediates the improvement of platelet production.
桡骨缺如伴血小板减少症的特征为双侧桡骨发育不全伴血小板减少。由于血小板生成素信号受损，骨髓巨核细胞数量较少且不成熟；随着时间的推移，血小板生成缺陷会有所改善。所有患者均存在 1q21 染色体微缺失，但这并不足以形成桡骨缺如伴血小板减少症。我们旨在对该综合征的信号缺陷进行细化研究。
我们报告了对 23 名患有桡骨缺如伴血小板减少症的儿科和成年患者进行的扩展研究，以通过免疫印迹和凝胶电泳迁移分析来仔细研究血小板生成素信号转导。此外，通过流式细胞术分析血小板免疫表型和反应性。将结果与包括年龄和血小板计数在内的临床数据相关联。
确定了两种不同的信号模式。青少年患者表现出血小板生成素信号转导阻断（模式#1），而成年人则恢复（模式#2）。磷酸化 Jak2 表明 STAT1、3 和 5、Tyk2、ERK 和 Akt 的激活，表明其在不同的血小板生成素依赖性途径中发挥关键作用。Jak2 cDNA 未发生突变，血小板上存在血小板生成素受体。患者的所有血小板均表达正常水平的 CD41/61、CD49b 和 CD49f 受体，而 CD42a/b 和 CD29 略有减少，纤维连接蛋白受体 CD49e 明显减少。对凝血酶受体激活肽的溶酶体颗粒释放减少。
我们显示在桡骨缺如伴血小板减少症中存在血小板生成和功能的综合缺陷。大多数患者在生命的最初几年中血小板升高，这先于在更晚的年龄检测到恢复的血小板生成素信号，这意味着这些事件是解耦的，并且未知的因素介导了血小板生成的改善。
