Abstract Number: PB1488
Meeting: ISTH 2020 Congress
Background: Patients with RUNX1 mutations have thrombocytopenia, impaired platelet function, and decreased granule contents and secretion. Our studies in a patient with RUNX1 mutation showed that platelet albumin and was decreased (Sun et al, Blood103: 948-54, 2004). Human platelets alpha granules contain numerous proteins, including PF4 and VWF, which are synthesized by megakaryocytes (MK), and others (fibrinogen, albumin and IgG) that are not synthesized but incorporated by endocytosis.
Aims: To understand the mechanisms leading to decreased platelet albumin and granule defect in RUNX1 haplodeficiency (RHD).
Methods: We studied endocytosis of fluorescent-labeled albumin, fibrinogen and IgG using flow cytometry in washed platelet suspensions (0-90 min) and in PMA-treated megakaryocytic HEL cells (up to 24 hours).
Results: In normal platelets the protein uptake was time- and concentration-dependent. The uptake of albumin, fibrinogen and IgG was decreased in father and daughter (both with RHD), with the mean fluorescent intensity (MFI) decreased > 50% of that in normal platelets. In HEL cells, uptake of albumin and fibrinogen was time- and concentration-dependent, with marked increased between 120 min and 24 hrs. In contrast to the findings in platelets, on siRNA RUNX1 knockdown the uptake/retention of albumin and fibrinogen was higher than in control siRNA cells at 120 min and 24 hrs.
Conclusions: This is first evidence that platelets with RUNX1 haplodeficiency have defective endocytosis of albumin, fibrinogen and IgG. The handling of these proteins by platelets and megakaryocytic cells is different and it is altered with RUNX1 knockdown in MK cells. These studies provide insights in to diverse a-granule abnormalities in RHD and into the handling of proteins by platelets and MK about which little is known.
To cite this abstract in AMA style:Del Carpio-Cano F, Mao G, Goldfinger L, Wurtzel J, Rao AK. Defective Endocytosis of Albumin, Fibrinogen and IgG in Platelets with RUNX1 Haplodeficiency [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/defective-endocytosis-of-albumin-fibrinogen-and-igg-in-platelets-with-runx1-haplodeficiency/. Accessed January 28, 2022.
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