title: Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function.
abstract: Procoagulant platelets exhibit hallmark features of apoptotic cells, including membrane blebbing, microvesiculation, and phosphatidylserine (PS) exposure. Although platelets possess many well-known apoptotic regulators, their role in regulating the procoagulant function of platelets is unclear. To clarify this, we investigated the consequence of removing the essential mediators of apoptosis, Bak and Bax, or directly inducing apoptosis with the BH3 mimetic compound ABT-737. Treatment of platelets with ABT-737 triggered PS exposure and a marked increase in thrombin generation in vitro. This increase in procoagulant function was Bak/Bax- and caspase-dependent, but it was unaffected by inhibitors of platelet activation or by chelating extracellular calcium. In contrast, agonist-induced platelet procoagulant function was unchanged in Bak(-/-)Bax(-/-) or caspase inhibitor-treated platelets, but it was completely eliminated by extracellular calcium chelators or inhibitors of platelet activation. These studies show the existence of 2 distinct pathways regulating the procoagulant function of platelets.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yuan
authors.forename: Emma C
authors.initials: EC
authors.lastname: Josefsson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: White
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.forename: Kylie D
authors.initials: KD
authors.lastname: Mason
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.forename: Katya J
authors.initials: KJ
authors.lastname: Henley
authors.forename: Akiko
authors.initials: A
authors.lastname: Ono
authors.forename: Sarah
authors.initials: S
authors.lastname: Hsiao
authors.forename: Abbey
authors.initials: A
authors.lastname: Willcox
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Hatem H
authors.initials: HH
authors.lastname: Salem
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D001777:Blood Coagulation; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D002118:Calcium; D020169:Caspases; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D006801:Humans; D010718:Phosphatidylserines / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494772:BAK1 protein, human; D002614:Chelating Agents; D010718:Phosphatidylserines; D010975:Platelet Aggregation Inhibitors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D013917:Thrombin; D020169:Caspases; D002118:Calcium