Platelet apoptosis by cold‐induced glycoprotein Ibα clustering

• Published in: Journal of thrombosis and haemostasis Vol. 8; no. 11; pp. 2554 - 2562
• Main Authors: VAN DER WAL, D. E., DU, V. X., LO, K. S. L., RASMUSSEN, J. T., VERHOEF, S., AKKERMAN, J. W. N.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2010
• Subjects: 14-3-3 Proteins - metabolism; 14‐3‐3; Acetylglucosamine - metabolism; Apoptosis; Bad; bcl-Associated Death Protein - metabolism; Binding Sites; Blood Platelets - cytology; Caspase 9 - metabolism; Cluster Analysis; Cold Temperature; cold‐storage; Flow Cytometry - methods; glycoprotein Ibα; Humans; Mitochondria - metabolism; Phosphorylation; platelet; Platelet Glycoprotein GPIb-IX Complex - metabolism; thromboxane A2; Thromboxane A2 - metabolism
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2010.04043.x

Background:  Cold‐storage of platelets followed by rewarming induces changes in Glycoprotein (GP) Ibα‐distribution indicative of receptor clustering and initiates thromboxane A2‐formation. GPIbα is associated with 14‐3‐3 proteins, which contribute to GPIbα‐signaling and in nucleated cells take part in apoptosis regulation. Objectives and methods:  We investigated whether GPIbα‐clustering induces platelet apoptosis through 14‐3‐3 proteins during cold (4 h 0 °C)‐rewarming (1 h 37 °C). Results:  During cold‐rewarming, 14‐3‐3 proteins associate with GPIbα and dissociate from Bad inducing Bad‐dephosphorylation and activation. This initiates pro‐apoptosis changes in Bax/Bcl‐xL and Bax‐translocation to the mitochondria, inducing cytochrome c release. The result is activation of caspase‐9, which triggers phosphatidylserine exposure and platelet phagocytosis by macrophages. Responses are prevented by N‐acetyl‐d‐glucosamine (GN), which blocks GPIbα‐clustering, and by O‐sialoglycoprotein endopeptidase, which removes extracellular GPIbα. Conclusions:  Cold‐rewarming triggers apoptosis through a GN‐sensitive GPIbα‐change indicative of receptor clustering. Attempts to improve platelet transfusion by cold‐storage should focus on prevention of the GPIbα‐change.