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Background

RUNX1 haplodeficiency is associated with thrombocytopenia, platelet dysfunction and a predisposition to acute leukaemia. Platelets possess three distinct types of granules and secretory processes involving dense granules (DG), α-granules and vesicles or lysosomes containing acid hydrolases (AH). Dense granules and granule deficiencies have been reported in patients with RUNX1 mutations. Little is known regarding the secretion from AH-containing vesicles.

Methods and results

We studied two related patients with a RUNX1 mutation, easy bruising, and mild thrombocytopenia. Platelet aggregation and 14 C serotonin in platelet-rich plasma (PRP) 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. Dense granules secretion on stimulation of gel-filtered platelets with thrombin and divalent ionophore A23187 (4-12 μmol L-1 ) were diminished. β-thromboglobulin and AH secretion was impaired in response to thrombin or A23187. We studied thromboxane-related pathways. The incorporation of 14 C -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 PRP was normal, suggesting that the defective secretion was not due to impaired thromboxane production.

Conclusions

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."xsd:string
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http://purl.uniprot.org/citations/28662545http://purl.uniprot.org/core/author"Poncz M."xsd:string
http://purl.uniprot.org/citations/28662545http://purl.uniprot.org/core/author"Rao A.K."xsd:string
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http://purl.uniprot.org/citations/28662545http://purl.uniprot.org/core/title"Defective acid hydrolase secretion in RUNX1 haplodeficiency: Evidence for a global platelet secretory defect."xsd:string
http://purl.uniprot.org/citations/28662545http://purl.uniprot.org/core/volume"23"xsd:string
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