Hyperthermia inhibits platelet haemostatic functions and selectively regulates the release of alpha-granule proteins.

ETULAIN J; LAPPONI MJ; PATRUCCHI SJ; ROMANIUK MA; BENZADÓN R; KLEMENT GL; NEGROTTO S; SCHATTNER M

JOURNAL OF THROMBOSIS AND HAEMOSTASIS

WILEY-BLACKWELL PUBLISHING, INC

Año: 2011

1538-7933

Background: Hyperthermia is one of the main disturbances of homeostasis occurring during sepsis or hypermetabolic states such as cancer. Platelets are important mediators of the inflammation that accompany these processes, but very little is known about the changes in platelet function that occur at different temperatures. Objectives: To explore the effect of higher temperatures on platelet physiology. Methods: Platelet responses including adhesion, spreading (fluorescence microscopy), αIIbβ3 activation (flow cytometry), aggregation (turbidimetry), ATP release (luminescence), thromboxane A2 generation, alphaBgranule protein secretion (ELISA), and protein phosphorylation from different signaling pathways (immunoblotting) were studied. Results: Preincubation of platelets at temperatures higher than 37ºC (38.5ºB 42ºC) inhibited thrombinBinduced haemostasis including platelet adhesion, aggregation, ATP release, and thromboxane A2 generation. The expression of PBselectin and CD63, as well as vascular endothelial growth factor (VEGF) release were completely inhibited by hyperthermia, whereas von Willebrand factor (vWF) and endostatin levels remained substantially increased at high temperatures. This suggested that release of proteins from platelet granules is modulated not only by classical platelet agonists but also by microenvironmental factors. The observed gradation of response involved not only antiangiogenesis regulators, but also other cargo proteins. Some signaling pathways were more stable than others. While ERK1/2 and AKT phosphorylation were resistant to changes in temperature, Src, Syk, p38 phosphorylation as well as IkappaB degradation were decreased in a temperatureBdependent fashion. Conclusions: Higher temperatures, such as those observed with fever or tissue invasion, inhibit the haemostatic functions of platelets and selectively regulate the release of alphaBgranule proteins.