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Glycoprotein IIb/IIIa receptor
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Soon after identification of the platelet membrane glycoprotein (GP) IIb/IIIa receptor and due to its key role in platelet aggregation, it became the target of antithrombotic therapy. There are three intravenous glycoprotein IIb/IIIa receptor inhibitors (GPI) used in clinical practice, particularly in patients with acute coronary syndrome undergoin...
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... identification of the platelet membrane glycoprotein (GP) IIb/IIIa receptor in 1981, was a milestone in the understanding of thrombus formation. Because of its key role in the platelet aggregation, it quickly became the target of antithrombotic therapy. In 1994, the results of the EPIC trial demonstrated the efficacy of GP IIb/IIIa receptor blocade in reducing thrombotic complications. 1 Within the next five years three intravenous GP IIb/IIIa receptor inhibitors (GPI) were approved for the clinical practice, particularly in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). 2-6 These three drugs have similar antithrombotic properties, but differ with respect to pharmocodynamics, pharmacokinetics and off-target effects ( table 1). According to recent European guidelines on acute myocardial infarction in STEMI patients, GPI should be considered for bailout therapy if there is angiographic evidence of massive thrombus, slow or no-reflow or a thrombotic complication (class of recommendation IIa, level of evidence C). The aim of the current review is to summarize available knowledge concerning off- target effects of GPI. A search covering the period from January 1993 to May 2013 was conducted by two independent investigators using MEDLINE, CENTRAL and Google Scholar databases. Proceedings from the Scientific Sessions of the American College of Cardiology [], American Heart Association [], European Society of Cardiology [], Transcatheter Cardiovascular Therapeutics [] and EuroPCR [] were also considered. The following keywords were applied: "abciximab", "eptifibatide", "tirofiban", "GP IIb/IIIa receptor inhibitor", "off-target effects". References of retrieved studies were searched manually for additional studies and reviews. No language restrictions were applied. It is well known, that platelet aggregation and thrombus formation play a pivotal role in acute coronary syndromes. 7-9 The rupture of atherosclerotic plaque initiates platelet adhesion, which is followed by platelets activation, including conformational changes in platelet structure, such as activation of the GP IIb/IIIa receptors and finally stimulation of platelet aggregation. The GP IIb/IIIa receptor belongs to the integrin family of adhesion molecules, composed of α and β subunit (figure 1). 10 After platelet activation the GP IIb/IIIa receptor develops a high affinity for the fibrinogen. The fibrinogen molecule has binding sites at both ends, allowing bridging between neighbouring platelets, leading to the thrombus formation. 11 The GPI prevent the binding of fibrinogen to adjacent GP IIb/IIIa receptors. 12 By this mechanism, the final common pathway of platelet aggregation is blocked. There are three intravenous GPI that are used in everyday practice, namely abciximab, and the small molecules eptifibatide and tirofiban. Abciximab is a part-murine, part-human chimeric Fab fragment of the monoclonal 7E3 IgG3 antibody against the GP IIb/IIIa receptor. Its structure was based on a murine monoclonal antibody, first described by Coller. 13-14 Abciximab is a competitive GP IIb/IIIa receptor inhibitor, it is bound to platelets with very high affinity, but reversibly. It is characterized by a short plasma half-life due to its rapid binding to platelet receptor. The binding site of abciximab is located on the beta 3 chain of the GP IIb/IIIa receptor. 15 High local concentration of abciximab obtainable with intracoronary administration despite decrease in platelet activity results also in the dissolution of existing platelet-rich thrombi and extensive dispersion of platelet aggregates reducing distal microembolization. 16-18 Inhibition of platelet-induced thrombin generation observed with high concentration of abciximab results in a decreased release of platelet granule containing inhibitors of fibrinolysis such as plasminogen activator inhibitor-1 and α2-anti-plasmin. 19 Increased porosity of thrombus caused by c7E3 Fab allows penetration of endogenous fibrinolytic agents into the clot, thereby promoting spontaneous thrombolysis. 18 In contrast to other GP IIb/IIIa inhibitors, abciximab is a non-selective GP IIb/IIIa receptor antagonist . Since the beta 3 subunit is also present in integrin αvβ3, abiximab also binds to this cellular vitronectin receptor expressed on endothelial and smooth muscle cells, monocytes, polymorphonuclear leukocytes, and T lymphocytes 19-21 . Abciximab also cross- reacts with the leukocyte-associated integrin Mac-1 (αMβ2). IC administration producing high local concentration of abciximab may also enhance the non-GP IIb/IIIa properties of this agent that are mainly based on complex anti-inflammatory interactions. Off-target effects of abciximab are a consequence of these cooperations. The endothelial integrin αvβ3 can bind to several molecules such as fibrinogen, vitronectin, thrombospondin and prothrombin, it also causes endothelial adhesion of activated platelets and entrapment of leukocytes in the platelet-fibrin mesh. It is upregulated in case of ischemia, predominantly in small arterioles. As an antagonist of integrin αvβ3, abiciximab may influence restenosis, by preventing αvβ3-mediated effects, including smooth muscle cell migration and proliferation, thrombin generation or clot retraction. Smooth muscle cell (SMC) migration and proliferation initiate the process of restenosis. 22 In the study by Baron and colleagues abiciximab inhibited adhesion and migration of SMC 23 , while Stouffer and coworkers described hindering influence of abciximab on SMC proliferation in the animal model. 24 Furthermore, the in-vitro study on human coronary artery SMC showed abciximab to be a potent inhibitor of human coronary artery SMC migration and invasion. 25 Therefore, αvβ3-mediated effects of abciximab on development of restenosis may explain the lower need for recurrent coronary interventions in the long term outcome in the EPIC trial. In addition, data from the EPISTENT and ISAR-SWEET trials suggested a reduction in clinical restenosis in favour of abciximab in diabetic patients. 26, 27 Similar results were observed in a large Danish single-center registry. 28 In a meta-anlysis by Wu and coworkers a decreased 1-year target lesion revascularization risk, was the only benefit from abciximab therapy. 29 However, these promising long-term results were not confirmed in the ERASER, EPILOG and CAPTURE trials. 2, 3, 30 Moreover, the beneficial effects on restenosis from abciximab therapy present in diabetic patients receiving coronary bare metal stents, were absent in diabetic patients undergoing elective drug-eluting stents implantation. 31 In a STRATEGY trial one group of patients received tirofiban plus sirolimus-eluting stent versus patients receiving abciximab plus bare metal stent. The occurrence of restenosis and the need for target vessel revascularization was significantly lower in patients receiving tirofiban plus sirolimus-eluting stent. 32 It suggests that reduction in clinical restenosis is less pronounced in patients treated with abciximab than in patients receiving drug-eluting stents. The addition of tirofiban to sirolimus-eluting stent seemed to be without any influence on restenosis, which was checked in the ADVANCE trial, where the administration of ...
Citations
... The presented data in (B-F) represent the mean ± standard error of the mean (n = 4). Antiplatelet drugs, including integrin α IIb β 3 antagonists, aspirin, and clopidogrel, are designed to prevent excessive platelet activation [9][10][11]. However, their efficacy is often hindered by side effects, like aspirin-induced gastric ulcers and bleeding, and clopidogrelassociated issues such as aplastic anemia and thrombocytopenic purpura [12,13]. ...
Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 μM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2–PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs.
... 2 The limitation in advancement often lies in the potential for inhibition of platelet function, resulting in increased bleeding, instability, or offtarget effects. [1][2][3][4][5] To address these challenges, we took advantage of an endogenous regulator of platelet function that targets the prostacyclin (IP) receptor. Recently, it was shown that platelets form the oxylipin 12(S)-hydroxy-eicosatrienoic acid through oxidation of the fatty acid dihomo-γ-linolenic acid by the enzyme 12-lipoxygenase. ...
Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12-HETrE, produced in the platelet, was shown to limit platelet reactivity through activation of the prostacyclin receptor. Here, we demonstrate the synthesis of a novel analogue of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk for bleeding. Human platelet activation was assessd by aggregometry, flow cytometry, western blot analysis, T-TAS, microfluidic perfusion chamber, and thromboelestography. Hemostasis, thrombosis, and bleeding assays were assessed in the mouse. CS585 was shown to potently target the prostacyclin receptor on the human platelet resulting in a highly selective and effective mechanism for prevention of platelet activation. Further, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk for bleeding in the mouse model. Hence, CS585 represents a new validated target in the treatment of thrombotic diseases without the risk of bleeding and off-target activation observed with other prostaglandin receptor agonists.
... The GP complex IIb/IIIa plays an essential role in the process of platelet adhesion by binding to fibrinogen, fibronectin, vitronectin and vWF [133]. The short-term obstruction of GP IIb/IIIa platelet with the use of intravenous agents has led to the development of an extensive range of GP IIb/IIIa oral antagonists, in the hope of expanding this benefit in the long-term treatment of patients with ACS. ...
The glycoprotein (GP) IIb/IIIa receptor is found integrin present in platelet aggregations. GP IIb/IIIa antagonists interfere with platelet cross-linking and platelet-derived thrombus formation through the competition with fibrinogen and von Willebrand factor. Currently, three parenteral GP IIb/IIIa competitors (tirofiban, eptifibatide, and abciximab) are approved for clinical use in patients affected by percutaneous coronary interventions (PCI) in the location of acute coronary syndrome (ACS). GP IIb/IIIa antagonists have their mechanism of action in platelet aggregation prevention, distal thromboembolism, and thrombus formation, whereas the initial platelet binding to damage vascular areas is preserved. This work is aimed to provide a comprehensive review of the significance of GP IIb/IIIa inhibitors as a sort of antiplatelet agent. Their mechanism of action is based on factors that affect their efficacy. On the other hand, drugs that inhibit GP IIb/IIIa already approved by the FDA were reviewed in detail. Results from major clinical trials and regulatory practices and guidelines to deal with GP IIb/IIIa inhibitors were deeply investigated. The cardiovascular pathology and neuro-interventional surgical application of GP IIb/IIIa inhibitors as a class of antiplatelet agents were developed in detail. The therapeutic risk/benefit balance of currently available GP IIb/IIa receptor antagonists is not yet well elucidated in patients with ACS who are not clinically evaluated regularly for early cardiovascular revascularization. On the other hand, in patients who have benefited from PCI, the antiplatelet therapy intensification by the addition of a GP IIb/IIIa receptor antagonist (intravenously) may be an appropriate therapeutic strategy in reducing the occurrence of risks of thrombotic complications related to the intervention. Development of GP IIb/IIIa inhibitors with oral administration has the potential to include short-term antiplatelet benefits compared with intravenous GP IIb/IIIa inhibitors for long-term secondary preventive therapy in cardiovascular disease. But studies showed that long-term oral administration of GP IIb/IIIa receptor inhibitors has been ineffective in preventing ischemic events. Paradoxically, they have been linked to a high risk of side effects by producing prothrombotic and pro-inflammatory events.
... Antiplatelet drugs help to reduce the risk of thrombotic events. Aspirin (a COX inhibitor), clopidogrel (ADP receptor antagonists) and GPIIb/IIIa receptor antagonists are the most prescribed drugs [20,21]. Nonetheless, their use is associated with several side effects, mainly a high risk of bleeding [20]. ...
This work focuses on the selection and the optimization of an efficient green-extraction method, used to recover a thymol-enriched extract from thyme (Thymus vulgaris L), as well as the evaluation of the inhibitory effect of this latter on the human platelet aggregation. Different innovative extraction techniques, namely bead milling extraction, ultrasound and microwave assisted extraction, were tested for their ability to recover a high added value extract from thyme. Among all tested eco-extraction techniques, microwave extraction (MAE) was the best method in term of its extraction yield (20.84% ± 0.51), thymol concentration (731.71 mg/g) and total phenolic (23.53 ± 1.83 mg (GAE)/g of extract) and flavonoid (6.22 ± 0.35 mg of QE/g of extract) contents. Moreover, thyme extract obtained by microwave assisted extraction (TMAE) showed the most active antioxidant effect comparing to the other tested extracts. Based on these results, TMAE was chosen to be evaluated for its antiplatelet effect. Thereby, arachidonic acid, collagen and ADP were used to induce the platelet aggregation on human platelet rich plasma taken from healthy controls and results revealed that TMAE strongly inhibited the induced platelet aggregation. Indeed, TMAE exhibited potent antiaggregant activity by inhibiting platelet activation, secretion and aggregation. Additionally, cytotoxicity assay on normal HEK-293 cells showed that TMAE has no cytotoxic effect even at high concentration (8 mg/ml) and can further be taken up to various biomedical applications mainly in the prevention of cardiovascular diseases.
... of fibrinogen receptors, a complex modulation by other factors, or the presence of GPIIb/IIIa receptors on various cells [54]. ...
Antithrombotic drugs are widely used for primary and secondary prevention, as well as treatment of many cardiovascular disorders. Over the past few decades, major advances in the pharmacology of these agents have been made with the introduction of new drug classes as novel therapeutic options. Accumulating evidence indicates that the beneficial outcomes of some of these antithrombotic agents are not solely related to their ability to reduce thrombosis. Here, we review the evidence supporting established and potential pleiotropic effects of four novel classes of antithrombotic drugs, adenosine diphosphate (ADP) P2Y12-receptor antagonists, Glycoprotein IIb/IIIa receptor Inhibitors, and Direct Oral Anticoagulants (DOACs), which include Direct Factor Xa (FXa) and Direct Thrombin Inhibitors. Specifically, we discuss the molecular evidence supporting such pleiotropic effects in the context of cardiovascular disease (CVD) including endothelial dysfunction (ED), atherosclerosis, cardiac injury, stroke, and arrhythmia. Importantly, we highlight the role of DOACs in mitigating metabolic dysfunction-associated cardiovascular derangements. We also postulate that DOACs modulate perivascular adipose tissue inflammation and thus, may reverse cardiovascular dysfunction early in the course of the metabolic syndrome. In this regard, we argue that some antithrombotic agents can reverse the neurovascular damage in Alzheimer’s and Parkinson’s brain and following traumatic brain injury (TBI). Overall, we attempt to provide an up-to-date comprehensive review of the less-recognized, beneficial molecular aspects of antithrombotic therapy beyond reduced thrombus formation. We also make a solid argument for the need of further mechanistic analysis of the pleiotropic effects of antithrombotic drugs in the future.
... Abciximab is a Fab fragment of the chimeric human-murine monoclonal antibody 7E3 and targets both integrin αIIbβ3 and αvβ3 [121,122]. Abciximab remains in circulation for at least two weeks with the normal recovery of platelet functions within 48 hours [123]. Eptifibatide, a cyclic heptapeptide based on the recognition se- quence found in snake venom, binds reversibly to integrin αIIbβ3, and has a half-life of 4-5 hours. ...
The risks for adverse thrombotic events, including myocardial infarction,
stroke, and deep vein thrombosis, are markedly increased
in dyslipidemia and other metabolic disorders and are the major
cause of death worldwide. Recent evidence points out that increased
thrombotic risk in dyslipidemia is mediated by platelets circulating
in a pre-activated state. The mechanisms of platelet reactivity
in this setting are multifaceted including platelet activation by
classic agonist receptor signaling as well as platelet sensitization
by pattern recognition receptors. Elevated platelet counts in dyslipidemia
due to dysregulation in hematopoiesis also contribute to
the overall thrombotic phenotype. Despite recent advancements in
antiplatelet and anticoagulation therapies, recurrences of adverse
thrombotic events remain to be a large clinical burden. In the light
of new knowledge, understanding mechanisms that drive pathologic
thrombosis in dyslipidemia, the antithrombotic approach shall be revisited.
Here, we discuss potential therapeutic avenues based on the
overview of platelet signaling mechanisms that contribute to a prothrombotic
phenotype in dyslipidemia.
... In everyday clinical practice we use three intravenous GP IIb/IIIa inhibitors: abciximab, eptifibatide, and tirofiban. Beside potent antiplatelet effect they can exert some off-target actions, mainly anti-inflammatory (26). The use of GP IIb/IIIa antagonists should be reserved for bail-out situations, if there is evidence of no-reflow or a thrombotic complication (class of recommendation IIa, level of evidence C) (12). ...
Antiplatelet therapy with P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor, cangrelor) is a cornerstone of medical therapy after percutaneous coronary interventions. Significant prevalence of high on-treatment platelet reactivity (HTPR) on clopidogrel treatment led to introduction of more potent P2Y12 inhibitors: prasugrel (a third generation thienopyridine), ticagrelor, and cangrelor (cyclopentyl-triazolo-pyrimidines). Nevertheless, more potent platelet inhibition and resulting low on-treatment platelet reactivity (LTPR) has led to increased risk of major bleeding events. These limitations resulted in a need for an individualized antiplatelet therapy approach. This review discusses the current role and future perspectives of diagnostic tools such as platelet function testing to optimize antiplatelet therapy with a focus on deescalating therapies to reduce bleeding risks.
... Their main therapeutic use is to prevent vascular thromboembolic events [1]. Cyclooxygenase inhibitors [2], adenosine diphosphate (ADP) receptor antagonists [3], and glycoprotein (GP) IIb/IIIa receptor antagonists [4] are the most commonly prescribed antiplatelet agents. Responses to these drugs vary, and their use is associated with a risk of bleeding. ...
Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10–80 μM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2–PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases.
... Activation of the P2Y 1 receptor by ADP initiates a weak and transient phase of platelet aggregation whereas binding of ADP to the P2Y 12 amplifies dense granule secretion, expression of P-selectin and platelet aggregation [8]. Further stimulation of the P2Y 12 receptor sustains the activation of the GP IIb/IIIa and GP Ia/IIa receptors and stabilization of platelet aggregates [9,10]. ...
Antiplatelet therapy with P2Y12 receptor inhibitors has become the cornerstone of medical treatment in patients with acute coronary syndrome, after percutaneous coronary intervention and in secondary prevention of atherothrombotic events. Clopidogrel used to be the most broadly prescribed P2Y12 receptor inhibitor with undisputable benefits especially in combination with aspirin, but a considerable number of clopidogrel-treated patients experience adverse thrombotic events in whom insufficient P2Y12-inhibition and a consequential high on-treatment platelet reactivity is a common finding. This clinically relevant limitation of clopidogrel has driven the increased use of new antiplatelet agents. Prasugrel (a third generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo-pyrimidine) feature more potent and predictable P2Y12-inhibition compared to clopidogrel, which translates into improved ischemic outcomes. However, excessive platelet inhibition and consequential low on-treatment platelet reactivity comes at the price of increased risk of major bleeding. The majority of randomized clinical trials failed to demonstrate improved clinical outcomes with platelet function testing and tailored antiplatelet therapy, but results of all recent trials of potent antiplatelets and prolonged antiplatelet durations point towards a need for individualized antiplatelet approach in order to decrease thrombotic events without increasing bleeding. This review focuses on potential strategies for personalizing antiplatelet treatment.
... Tirofiban is a non-peptide agent and irreversible antagonist of major thrombotic surface aggregation factor, GP IIb/IIIa and is an antiaggregant agent and is frequently used in coronary artery disease. Many randomized controlled studies reported that tirofiban is a potent inhibitor of thrombocyte aggregation and it prevents arterial thrombosis (7,8) . ...
Introduction: Tissue perfusion plays an important role in pancreatitis. Free oxygen radicals also have some triggering roles
in the severity of acute pancreatitis. Tirofiban hydrochloride (TH) is being used for ischemic disorders for many years and is known
as an antiaggregant drug. We aimed to determine the therapeutic effects of tirofiban in cerulein-induced acute pancreatitis in this
animal study.
Materials and methods: Twenty-four Wistar-Albino male rats were divided into three equal groups; Group I: Sham-operated
group, Group II: cerulein induced pancreatitis group, Group III: cerulein induced pancreatitis + treatment group (intraperitoneal
0.25 mg tirofiban hydrochloride in 1 ml isotonic saline solution). Amylase and lipase levels were studied in blood samples and
malondialdehyde, glutathione peroxidase and superoxide dismutase activities were measured in tissue samples.
Results: Amylase and lipase levels were elevated in acute pancreatitis group. The levels of both enzymes were decreased after
the rats were medicated with TH. Malondialdehyde (MDA) was higher in pancreatitis group without treatment. There were no
significant differences between groups according to glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) levels.
Conclusion: The present findings suggest that TH has an antiaggregant effect and may reduce the progression and improve
the healing of acute pancreatitis.
Key words: Acute pancreatitis, reactive oxygen species, Tirofiban hydrochloride, Glycoprotein IIb-IIIa inhibitor.
