Effect of 5‐HT2A receptor antagonists on human platelet activation in blood exposed to physiologic stimuli and atherosclerotic plaque

Abstract

To cite this article: Bampalis VG, Dwivedi S, Shai E, Brandl R, Varon D, Siess W. Effect of 5-HT 2A receptor antagonists on human platelet activation in blood exposed to physiologic stimuli and atherosclerotic plaque. J Thromb Haemost 2011; 9: 2112-5.New antiplatelet therapies are needed, because the two types of clinically used platelet inhibitors, i.e. the cyclo-oxygenase-1 inhibitor aspirin and P2Y 12 receptor antagonists (clopidogrel and prasugrel), even in combination, are not optimal in preventing major atherothrombotic events, and are associated with increased bleeding [1,2]. Concerning this challenge, a recent study, published in this journal, has reported encouraging results showing that 5-HT 2A receptor inhibition by a new antagonist (APD791) improves coronary patency in the in vivo canine model [3].5-HT 2A receptor antagonists have been long known to inhibit 5-hydroxytryptamine (5-HT)-dependent platelet aggregation [4][5][6][7][8]; however, they have not been successfully introduced as antiplatelet agents in the clinic. 5-HT stored in platelet-dense granules and released from them upon platelet stimulation might serve as a feedback mediator by binding to 5-HT 2A receptors on the platelet surface and support platelet aggregation [9]. Indeed, 5-HT added exogenously to plateletrich plasma (PRP) or blood synergizes with several platelet stimuli in inducing platelet aggregation [5,6,8,10]. A short survey of the literature shows that 5-HT 2A receptor antagonists have unequivocally been shown to inhibit 5-HT-potentiated platelet aggregation of PRP in humans and many other species in vitro and ex vivo [3,6,8,11,12] and 5-HT-stimulated thrombus formation in mice in vivo [13]. There are also animal studies reporting inhibition of aggregation induced by physiologic platelet stimuli (collagen, thrombin, ADP, and epinephrine) by 5-HT 2A receptor antagonists in vitro and ex vivo, and in thrombosis models in vivo, particularly in the Folts model of coronary occlusion in the dog [3,11,12,[14][15][16][17]. However, the results in humans are conflicting [5,[18][19][20].In light of the conflicting results reported in the literature and the recent study in dogs, we decided to perform, for the first time, a comprehensive study of the effects of 5-HT 2A antagonists on platelets in human blood in vitro under static and arterial flow conditions, after stimulation with physiologic agonists and a pathophysiologically relevant platelet agonist, i.e. human atherosclerotic plaque homogenate.We studied three different 5-HT 2A receptor antagonists: ketanserin [21], R-96544 [12], and sarpogrelate [22]. Sarpogrelate is a drug introduced clinically as a therapeutic agent for the treatment of peripheral artery occlusive disease [23]. It has been shown recently that sarpogrelate treatment inhibits 5-HTpotentiated platelet aggregation in patients with ischemic stroke [24].Hirudin-anticoagulated blood from healthy volunteers was used in all experiments. Multiple electrode aggregometry was used to measure platelet aggregation in blood (Dyn...

The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

“…To this end, several potent and selective antagonists of the 5-HT 2A receptor were developed and tested and have demonstrated antiplatelet and antithrombotic activities [29], [39]–[44]. Unfortunately however, none of these molecules has made it into clinical practice, at least in the context of thrombogenesis [5], [9], [24]. Consequently, we decided to investigate whether the aforementioned antidepressant 5-HT 2A receptor antagonists may be repurposed for antiplatelet therapy [25], [26], [41].…”

“…Analysis revealed that while clopidogrel treatment did significantly prolonged occlusion times, its magnitude did not significantly differ from that observed in cyproheptadine-, and pizotifen- treated mice. Given their different target receptors (clopidogrel on P2Y 12 receptors) these 5-HT 2A receptor antagonist may be able to serve as alternative medications, or complement to clopidogrel, given that dual therapy with clopidogrel is common clinical practice for thromboprotection [9], [46], [47].…”

“…Upon platelet activation at the site of vessel injury, 5-HT is released from the dense granules in platelets. Serotonin or 5-HT by itself is a weak activator of platelet aggregation but it amplifies aggregation induced by other agonists including collagen, ADP, and epinephrine [8], [9]. Previous studies have shown a significant serotonin-dependent increase in platelet aggregation in depressed patients compared with controls, indicating serotonin plays an important role in the genesis of occlusive diseases [10], [11].…”

Inhibition of platelet aggregation and thrombosis by indole alkaloids isolated from the edible insect Protaetia brevitarsis seulensis (Kolbe)

“…Platelets are activated by several agonists that bind to specific platelet membrane receptors . Serotonin (5‐hydroxytryptamine, 5‐HT) facilitates the development of platelets with increased pro‐coagulant activity and potentiates platelet activation, resulting in converging signal transduction pathways that would be responsible for blood coagulation . This implies that modulation of serotonin‐mediated responses may offer a therapeutic target for the development of anticoagulant agent.…”

Use of microfluidics to assess the platelet-based control of coagulation

“…In patients with unstable coronary syndrome, treatment with the antiplatelet agent abciximab (integrin α IIb β 3 antagonist) suppressed both platelet and fibrin accumulation [33]. Even antidepressant treatment targeting serotonin signaling reduced fibrin formation [34] and suppressed thrombus formation on plaque material [35]. Blood flow was an important factor in the lysis of fibrin fibers around thrombi, in which PS-exposing platelets had a key role in plasminogen activation (the main fibrinolysis mediator) [12].…”