Changes in platelet Bax levels contribute to impaired platelet response to thrombin after cardiopulmonary bypass: prospective observational clinical and laboratory investigations

• Published in: British journal of anaesthesia : BJA Vol. 119; no. 6; pp. 1118 - 1126
• Main Authors: Murase, M., Nakayama, Y., Sessler, D.I., Mukai, N., Ogawa, S., Nakajima, Y.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2017; Oxford University Press
• Subjects: Aged; Aged, 80 and over; anaesthesia; Apoptosis; bcl-2-Associated X Protein - blood; bcl-2-Associated X Protein - genetics; blood platelet disorders; Blood Platelets - pathology; Blotting, Western; Cardiopulmonary Bypass; Female; Flow Cytometry; Humans; intracellular signaling peptides and proteins; Male; Middle Aged; Platelet Activation; Platelet Aggregation; platelet membrane glycoproteins; Postoperative Complications - blood; Postoperative Complications - pathology; Prospective Studies; Thrombin - pharmacology; platelet membrane glycoproteins; apoptosis; blood platelet disorders; intracellular signaling peptides and proteins; anaesthesia
• ISSN: 0007-0912; 1471-6771; 1471-6771
• DOI: 10.1093/bja/aex349

Anucleate platelets can undergo apoptosis in response to various stimuli, as do nucleated cells. Cardiopulmonary bypass (CPB) causes platelet dysfunction and can also activate platelet apoptotic pathways. We therefore evaluated time-dependent changes in blood platelet Bax (a pro-apoptotic molecule) levels and platelet dysfunction after cardiac surgery. We assessed blood samples obtained from subjects having on-pump or off-pump coronary artery bypass graft surgery (n=20 each). We also evaluated the in vitro effects of platelet Bax increase in eight healthy volunteers. Thrombin-induced platelet calcium mobilisation and platelet-surface glycoprotein Ib (GPIb) expression were lowest at weaning from CPB and did not recover on postoperative day one. On-pump surgery increased platelet expression of Bax, especially the oligomerised form, along with translocation of Bax from the cytosol to mitochondria and platelet-surface tumour necrosis factor-alpha (TNF-α)–converting enzyme (TACE) expression. In contrast, mitochondrial cytochrome c expression was reduced. While similar in direction, the magnitude of the observed changes was smaller in patients having off-pump surgery. In vitro, a cell-permeable Bax peptide increased platelet Bax expression to the same extent seen during bypass and produced similar platelet changes. These apoptotic-like changes were largely reversed by Bcl-xL pre-administration, and were completely reversed by combined application of inhibitors that stabilise outer mitochondrial membrane permeability and TACE. CPB increases platelet Bax expression, which contributes to reduced platelet-surface GPIb expression and thrombin-induced platelet calcium changes. These changes in platelet apoptotic signalling might contribute to platelet dysfunction after CPB. UMIN Clinical Trials Registry (number UMIN000006033).