Serotonergic mechanisms enhance platelet-mediated thrombogenicity

Abstract

Although it is generally acknowledged that serotonin (5-HT) is a weak agonist for human platelets, recent information suggests an association between serotonergic mechanisms and cardiovascular risk. We investigated the action of 5-HT on adhesive, cohesive and procoagulant properties of human platelets. Impact of 5-HT on whole blood coagulation and thrombin generation was measured by modified thromboelastometry (TEM) and specific fluorogenic assays. We evaluated the effects of 5-HT on thrombus formation in an in-vitro model of thrombosis using human flowing blood. In platelet-rich plasma (PRP), 5-HT favoured the expression of CD62-P, and procoagulant molecules on platelet membranes. These effects were potentiated in the presence of Ca(++) and/or ADP. Incubation with 5-HT accelerated clotting times and augmented clot strength in whole blood TEM, and enhanced thrombin generation in PRP. In perfusion studies, 5-HT significantly increased fibrin deposition at low shear (300s(-1)) and enhanced platelet thrombus formation on the damaged vascular surface at high shear (1,200s(-1)). Selective inhibition of serotonin reuptake (SSRI) attenuated effects of 5-HT on platelet activation and downregulated the prothrombotic tendencies observed in the previous experimental conditions. In general, reductions of thrombogenic patterns observed with SSRI were more evident under shear conditions (aggregation and perfusion systems) and less evident under steady conditions (TEM and thrombin generation assays). In conclusion, 5-HT is not a weak agonist for human platelets; instead it accentuates platelet activation, potentiates procoagulant responses on human blood and increases thrombogenesis on damaged vascular surfaces. The remarkable antithrombotic actions achieved through SSRI deserve further mechanistic and clinical investigations.

Role of platelets in neuroinflammation: a wide-angle perspective

“…Platelet SERT density correlated closely with P-selectin expression, a marker of platelet activation and cell-cell interaction, consistent with the concept of 5HT as a weak agonist [265]. However, Galan et al concluded that, contrary to tradition, 5HT is not a weak agonist of platelets, but instead sensitizes them or potentiates their responsiveness [266]. …”

“…The relative potency may be misleading since it is based on data in vitro whereas in vivo several of these agonists, especially the "weak" ones, can act synergistically to potentiate or "prime" responses to others [5]. For example, serotonin [266,319]; and vWF-induced aggregation requires co-stimulation (including by ristocetin, an antibiotic used in laboratory studies) or conformation change of vWF. Information on the GPCR's is simplified from Ch.…”

Selective Serotonin Reuptake Inhibitors and Operative Bleeding Risk

“…Serotonin is essential to normal platelet function. A critical component of platelet activation is serotonin secretion, which has a number of different effects, including: 1) strong vasoactive properties through direct action on serotonin receptors and nitric oxide production, 2) the potentiation of the aggregation induced by adenosine diphosphate, epinephrine and collagen, and 3) the enhancement of fibrin formation (12–15). …”

Serotonin Antagonism Improves Platelet Inhibition in Clopidogrel Low-Responders after Coronary Stent Placement: An In Vitro Pilot Study

“…Serotonin is a weak platelet activator promoting hemostasis by enhancing platelet alpha granule release and by enhancing plasmatic coagulation [17], [18], [19], [20]. Together with ADP, serotonin is stored in platelet dense granules (at millimolar concentrations) and released upon platelet activation, locally reaching micromolar levels at sites of coronary atherothrombosis [21], [22], [23].…”

“…Released serotonin is also a potent vasoconstrictor of coronary arteries with damaged endothelium [24]. Serotonin antagonism as well as platelet serotonin depletion by treatment with selective serotonin reuptake inhibitors have both been associated with a reduction in arterial thrombogenicity [17], [25], [26]. Therefore, serotonin antagonism in addition to established therapies might be a promising approach to improve the treatment of CAD patients.…”