Abstract Number: LPB0035
Meeting: ISTH 2021 Congress
Background: Platelets are short-lived anucleate cells that play an essential role in primary hemostasis. The fast pace of platelet lifespan emphasizes the need for a tight regulatory mechanism to avoid spontaneous bleeding or arterial occlusion.
Aims: Here, we investigate the functional relationship between the two well-established mechanisms that regulate platelet survival: desialylation and apoptosis.
Methods: Biotinylated old and young platelet subpopulations were obtained 60hs after biotin injection of WT mice followed by immunomagnetic separation. Platelets from the old (biotin+) fraction were highly desialylated, with increased levels of phosphatidylserine and Neu1 (sialidase) surface exposure compared to the young (biotin–) platelets. These data suggest platelets become desialylated and subsequently undergo apoptosis in circulation.
Results: Next, we performed BH3 profiling to measure mitochondrial readiness to undergo apoptosis on two different models of desialylated platelets (Asgr2-/- and St3gal4-/- mice) and compared to WT mice treated with the sialidase inhibitor, DANA. We found that both models of desialylated platelets were more primed to undergo apoptosis compared to WT, which was consistent with increased levels of apoptosis detected with Annexin V and blotting for cleaved caspase 3. Notably, DANA-treated platelets were less primed than WT, indicating that sialidase inhibition suppresses platelet apoptosis. Platelet dependence on the pro-survival protein BCL-XL, which has been previously shown to be vital for platelet survival, was also reduced by DANA treatment. This has implications for the use of BCL-XL inhibitors for cancer therapy, which are known to cause on-target thrombocytopenia.
Conclusions: We also tested if apoptosis alone could induce desialylation. Neither in vivo nor in vitro treatment of WT platelets with the BCL-2/BCL-XL inhibitor ABT-737 affected platelet desialylation. Lastly, using galactose-binding lectin chromatography, we identified ß1 integrin as the major glycoprotein highly desialylated in whole cell lysates from biotinylated old (biotin+) WT platelets populations, as well as in desialylated platelets derived from Asgr2-/- and St3gal4-/- mice.
To cite this abstract in AMA style:Grozovsky R, Roweth H, Fraser C, Sarosiek K, Battinelli E. Desialylation Primes Platelets for Apoptosis: A New Role for ß1 Integrin [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/desialylation-primes-platelets-for-apoptosis-a-new-role-for-s1-integrin/. Accessed September 24, 2021.
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