Defective acid hydrolase secretion in RUNX1 haplodeficiency: Evidence for a global platelet secretory defect.
Defective acid hydrolase secretion in RUNX1 haplodeficiency: Evidence for a global platelet secretory defect.
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DOI：
10.1111/hae.13280
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Poncz M
中科院分区：
文献类型：
--
作者：
Rao AK;Poncz M
RUNX 1单倍缺陷与血小板减少症、血小板功能障碍和急性白血病易感性相关。血小板具有三种不同类型的颗粒和分泌过程，包括致密颗粒（DG）、α颗粒和含有酸性水解酶（AH）的囊泡或溶酶体。在RUNX 1突变患者中报告了DG和颗粒缺陷。关于含酸水解酶囊泡的分泌知之甚少。我们研究了两个相关的患者与RUNX 1突变，容易瘀伤，轻度血小板减少症。血小板聚集和富血小板血浆中的14 C-5-羟色胺在ADP、肾上腺素、胶原和花生四烯酸的作用下受损。DG（ATP、ADP）、α-颗粒（β-血小板球蛋白）和含AH囊泡（β-葡萄糖醛酸酶、β-氨基己糖苷酶、α-甘露糖苷酶）的含量正常或极轻微降低。用凝血酶和二价离子载体A23187（4-12 μM）刺激凝胶过滤的血小板时，DG分泌减少。β-凝血球蛋白和酸性水解酶的分泌在凝血酶或A23187的作用下受损。我们研究了血栓素相关通路。14 C-花生四烯酸掺入磷脂和随后的花生四烯酸释放凝血酶活化是正常的。血小板血栓素A2的生产在全血血清和凝血酶刺激的富血小板血浆是正常的，这表明有缺陷的分泌不是由于受损的血栓素生产。这些研究提供了RUNX 1突变患者AH（溶酶体）分泌缺陷的第一个证据，以及涉及所有三种类型的血小板颗粒的分泌缺陷，与颗粒含量缺乏无关。他们强调了与RUNX 1突变相关的多效性效应和多种血小板缺陷。
RUNX1 haplodeficiency is associated with thrombocytopenia, platelet dysfunction and a predisposition to acute leukemia. Platelets possess three distinct types of granules and secretory processes involving dense granules (DG), α–granules and vesicles or lysosomes containing acid hydrolases (AH). DG and granule deficiencies have been reported in patients with RUNX1 mutations. Little is known regarding the secretion from acid-hydrolase containing vesicles. We studied two related patients with a RUNX1 mutation, easy bruising, and mild thrombocytopenia. Platelet aggregation and 14C serotonin in platelet-rich plasma were impaired in response to ADP, epinephrine, collagen and arachidonic acid. Contents of DG (ATP, ADP), α–granules (β-thromboglobulin), and AH-containing vesicles (β-glucuronidase, β-hexosaminidase, α-mannosidase) were normal or minimally decreased. DG secretion on stimulation of gel-filtered platelets with thrombin and divalent ionophore A23187 (4–12 μM) were diminished. β-thromboglobulin and acid hydrolase secretion was impaired in response to thrombin or A23187. We studied thromboxane-related pathways. The incorporation of 14C-arachidonic acid into phospholipids and subsequent arachidonic acid release on thrombin activation was normal. Platelet thromboxane A2 production in whole blood serum and on thrombin stimulation of platelet-rich plasma was normal, suggesting that the defective secretion was not due to impaired thromboxane production. These studies provide the first evidence in patients with a RUNX1 mutation for a defect in AH (lysosomal) secretion, and for a global defect in secretion involving all three types of platelet granules that is unrelated to a granule content deficiency. They highlight the pleiotropic effects and multiple platelet defects associated with RUNX1 mutations.
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影响因子：
2.9
作者：
HOLMSEN, H;STORM, E;DAY, HJ
通讯作者：
DAY, HJ
影响因子：
4.1
作者：
HOLMSEN, H;KAPLAN, KL;DANGELMAIER, CA
通讯作者：
DANGELMAIER, CA
DOI：
10.1161/atvbaha.110.221879
发表时间：
2011-04-01
影响因子：
8.7
作者：
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10.9
作者：
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通讯作者：
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影响因子：
20.3
作者：
Jalagadugula, Gauthami;Mao, Guangfen;Rao, A. Koneti
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Rao, A. Koneti