Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function.
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.
Schoenwaelder
Simone M
SM
Australian Centre for Blood Diseases, Monash University, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
Yuan
Yuping
Y
Josefsson
Emma C
EC
White
Michael J
MJ
Yao
Yu
Y
Mason
Kylie D
KD
O'Reilly
Lorraine A
LA
Henley
Katya J
KJ
Ono
Akiko
A
Hsiao
Sarah
S
Willcox
Abbey
A
Roberts
Andrew W
AW
Huang
David C S
DC
Salem
Hatem H
HH
Kile
Benjamin T
BT
Jackson
Shaun P
SP
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
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