Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

Abdelmalik, N.; Ruhé, Henricus G.; Barwari, K.; Dool, E. J. van den; Meijers, Joost C. M.; Büller, Harry R.; Schene, A.H.; Kamphuisen, Pieter Willem

doi:10.1111/j.1538-7836.2008.03196.x

Cited by 33 publications

(31 citation statements)

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“…Chronic inhibition of SERT through selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopram and paroxetine) leads to dramatically reduced platelet 5-HT granule content (5,6), altering peripheral 5-HT homeostasis and potentially modifying multiple physiological processes including hemostasis (7)(8)(9)(10). Clinically, increased bleeding risk has been observed in patients taking SSRIs, and platelet aggregation is disrupted (5,11).…”

mentioning

confidence: 99%

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Oliver

Duvernay

Hamm

et al. 2016

Journal of Biological Chemistry

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Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. In the periphery, serotonin (5-HT) 3 is produced by enterochromaffin cells in the gastrointestinal tract, released into the plasma, and quickly taken up by platelets via the plasma membrane serotonin transporter (SERT). Following uptake, 5-HT is stored in dense granules by the actions of the vesicular monoamine transporter 2 (1-4). Chronic inhibition of SERT through selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopram and paroxetine) leads to dramatically reduced platelet 5-HT granule content (5, 6), altering peripheral 5-HT homeostasis and potentially modifying multiple physiological processes including hemostasis (7-10). Clinically, increased bleeding risk has been observed in patients taking SSRIs, and platelet aggregation is disrupted (5, 11). Here, we have characterized a similar effect in two distinct mouse models of lost SERT function, suggesting that sustained loss of SERT function influences hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERTPlatelet dense granules contain 5-HT along with other platelet agonists including adenosine diphosphate (ADP), thromboxane (TXA2), and histamine. Appropriate platelet activation depends on the timely release of these factors (4, 5, 12). Platelet aggregation is crucial early in thrombus formation (4, 5, 13). Aggregation, which is the bridging of platelet-platelet contacts, requires a conformational alteration in the glycoprotein ␣IIb␤3, leading to its activation and fibrinogen binding. 5-HT has been shown to enhance aggregation in a 5-HT 2A receptor (5-HT 2A R)-dependent manner (4, 14 -17). The 5-HT 2A R is the only serotonergic receptor found on platelets and potentiates platelet responses to weak agonists like ADP (18). Subthreshold concentrations of two different platelet agonists can exert a synergistic effect on platelet activation. One example includes dual ADP and 5-HT activation leading to increases in cytosolic [Ca 2ϩ ] (13). However, the role of 5-HT during in vivo hemostasis remains unclear, particularly in the context of chronic SERT inhibition.To elucidate the underlying mechanisms of SSRI effects on platelet aggregation, a better understanding of acute versus chronic inhibition of SERT function during platelet activation is required. Acute and chronic blockage of SERT function results in distinct scenarios regarding the effects on 5-HT homeostasis. Acute inhibition of SERT blocks the amount of

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mentioning

confidence: 99%

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Oliver

Duvernay

Hamm

et al. 2016

Journal of Biological Chemistry

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“…Mice implanted with osmotic mini-pumps were injected with PAR (3 mg/kg)1325 as a SERT inhibitor or Sarpogrelate (Sarpo, 30 mg/kg)171920 as a 5-HT 2A antagonist, either before the infusion of 5-HT started (pre-infusion), or at the end of 24-hr 5-HT infusion (post-infusion) (5 mice per group). The half-life of PAR is 24-hr but Sarpo is only 12-hr.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we were interested in determining the effects of individual drugs on platelet physiology, two types of SSRI, PAR and Citalopram (CIT)25, or 5-HT 2A antagonists, Sarpo and MDL10090726, or 5-HT, or cocaine at various concentrations were tested on platelets isolated from wild-type mice (Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

Effect of serotonin on platelet function in cocaine exposed blood

Ziu

Hadden

et al. 2014

Sci Rep

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5-hydroxytryptamine (5-HT) reuptake inhibitors counteract the pro-thrombotic effect of elevated plasma 5-HT by down-regulating the 5-HT uptake rates of platelets. Cocaine also down-regulates the platelet 5-HT uptake rates but in contrast, the platelets of cocaine-injected mice show a much higher aggregation rate than the platelets of control mice. To examine the involvement of plasma 5-HT in cocaine-mediated platelet aggregation, we studied the function of platelets isolated from wild-type and transgenic, peripheral 5-HT knock-out (TPH1-KO) mice, and cocaine-insensitive dopamine transporter knock in (DAT-KI) mice. In cocaine-injected mice compared to the control mice, the plasma 5-HT level as well as the surface level of P-selectin was elevated; in vitro platelet aggregation in the presence of type I fibrillar collagen was enhanced. However, cocaine injection lowered the 5-HT uptake rates of platelets and increased the plasma 5-HT levels of the DAT-KI mice but did not change their platelets aggregation rates further which are already hyper-reactive. Furthermore, the in vitro studies supporting these in vivo findings suggest that cocaine mimics the effect of elevated plasma 5-HT level on platelets and in 5-HT receptor- and transporter-dependent pathways in a two-step process propagates platelet aggregation by an additive effect of 5-HT and nonserotonergic catecholamine.

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“…20 mg paroksetinin oluþturduðu etki incelendiðinde kanama zamaný üzerine etki etmeden serotonin ve bthromboglobulin (b-TG) miktarýnda azalmaya yol açtýðý saptanmýþ . Bu etkinin dozdan baðýmsýz olduðu ve 5-HTTLPR SERT polimorfizminin bu etkilere aracýlýk ediyor olabileceði ileri sürülmüþtür (13).…”

Section: Tartiþmaunclassified

Ecchymosis Associated With The Use of Paroxetine: A Case Report

Ay¹

2017

J Clin Psy

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SUMMARYParoxetine is an antidepressant included in the group of selective serotonin reuptake inhibitors (SSRI) with antidepressant and anxiolytic properties. A rarely seen adverse effect of paroxetine is increase of bleeding tendency. There are several reports of ecchymoses, epistaxis, subconjunctival hemorrhage, lower and upper gastrointestinal bleeding related to paroxetine use. A case of a female patient who developed ecchymoses during paroxetine use is discussed in this paper.Key Words: Paroxetine, Ecchymosis , Depressive Disorder ÖZET Paroksetin, antidepresan ve anksiyolitik özellikleri olan seçici serotonin gerialým inhibitörü (SSGI) grubundan bir antidepresandýr. Paroksetine baðlý nadir görülen yan etki kanama eðiliminin artmasýdýr. Paroksetin kullanýmý ile iliþkili ekimoz, epistaksis, subkonjuctival kanama, alt ve üst gastrointestinal kanama ile ilgili olgu bildirimleri mevcuttur. Bu yazýda paroksetin kullanýmý sýrasýnda ekimoz geliþen bir kadýn hasta tartýþýlmýþtýr.

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Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

Abstract: Paroxetine 20 mg day(-1) does not increase overall bleeding time, but impairs platelet function by decreasing the levels of platelet serotonin and platelet ss-TG. These paroxetine effects appear to be mediated by 5-HTTLPR, with most pronounced effects in patients without L(A)-alleles.

Cited by 33 publications

References 33 publications

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Effect of serotonin on platelet function in cocaine exposed blood

Ecchymosis Associated With The Use of Paroxetine: A Case Report

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