Abstract 55: Chronic Loss of Serotonin Transporter Function Alters Platelet Adhesion and Spreading
Clinical observations indicate that patients taking selective serotonin reuptake inhibitors(SSRIs) have an increased risk of bleeding. However it remains unclear how SSRIs, which inhibit the serotonin transporter(SERT), modulate homeostasis and platelet activation. There are two primary mechanisms by which serotonin(5HT) affects platelet function: activation of the 5HT2A receptor and uptake by SERT. It has also been demonstrated that SERT regulates aIIbB3(GPIIbIIIa) function, the common signaling pathway in platelet activation and crucial for platelet aggregation. We sought to elucidate how the serotonergic system modulates aIIbB3 function by examining platelet spreading and attachment to immobilized fibrinogen. To model altered serotonergic tone, we used mice with a genetic deletion of SERT(SERT KO). As observed with SSRI use, the blood 5HT concentration in SERT KO mice is miniscule. We found that SERT KO mice display increased tail bleed time and thrombin time. Interestingly, SERT KO platelets showed reduced spreading but increased attachment on immobilized fibrinogen. 5HT(100nM) was able to rescue the reduced spreading on immobilized fibrinogen. To determine the mechanism, we examined platelet spreading with kentanserin(5HT2A antagonist) or citalopram(SSRI). We found that acute administration of citalopram did not alter spreading at physiologically relevant levels. Blockade of 5HT2A activation however, caused WT platelets to behave similarly to SERT KO with reduced spreading. Src is a tyrosine kinase that plays a major role in platelet spreading. Using in-cell western, P-Src(416) was decreased in SERT KO mice following spreading on immobilized. After addition of 5HT, P-Src(416) in SERT KO platelets was normalized to WT P-Src levels. Furthermore, treatment with ketanserin caused WT P-Src(416) to decreased to SERT KO P-Src(416) levels. These finding suggest that the peripheral serotonergic system is “recalibrated” in the absence of 5HT and leads to altered function of aIIbB3 via 5HT2A. From this data, we have elucidated a novel regulatory mechanism of 5HT for platelet fibrinogen binding that could regulate the recruitment of platelets by fibrinogen binding to a growing thrombus.
Author Disclosures: K.H. Oliver: None. M. Dohn: None. M. Duvernay: None. H. Hamm: None. A. Carnerio: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.