Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease

Glycoprotein IIb/IIIa inhibitors represent a new promising class of antiplatelet medications. Their use in acute coronary syndromes and for patients undergoing percutaneous coronary intervention has been the subject of a number of large controlled trials using both the intravenous and the oral forms. In this review, we present a systematic overview of these trials.     

Delayed thrombocytopenia following abciximab therapy

Inhibitors of glycoprotein (GP) IIb/IIIa are currently approved for the treatment of acute coronary syndromes and during performance of percutaneous coronary interventions (PCIs). More than 500 000 patients annually undergo PCIs in the USA alone. Of these, 35% are receiving GPIIb/IIIa inhibitors. Currently, three different intravenous GPIIb/IIIa inhibitors are commercially available. Profound thrombocytopenia occurs almost exclusively with abciximab. Usually thrombocytopenia develops within 24 hours following abciximab administration. This paper describes three patients who developed delayed profound thrombocytopenia, occurring five days following abciximab therapy. These cases of thrombocytopenia were self-limited and reversible. Absence of serious bleeding complications was noted. The pathophysiology, differential diagnosis, natural history and management of the coronary patients with abciximab-induced thrombocytopenia are discussed.     

Debate: PCI vs CABG: a moving target, but we are gaining

The treatment of patients with coronary artery disease continues to evolve; all three strategies – medical therapy, surgical revascularization, and percutaneous coronary intervention – have changed. Medical therapy with intense risk-factor modification and treatment with a statin, aspirin, and angiotensin-converting enzyme (ACE) inhibitors, should be used unless contraindicated. Surgical therapy has also changed with the introduction of minimally invasive, beating heart surgery. Percutaneous coronary intervention has perhaps changed the most radically with adjunctive therapy – glycoprotein IIb/IIIa inhibitors, thienopyridines, and reliance on stent implantation. The future, with new distal protection devices and drug-coated stents, should continue to see increased numbers of patients who can benefit from percutaneous intervention.     

低分子肝素与普通肝素对经皮冠脉介入手术的疗效和安全性的比较

目的:回顾性比较冠心病患者接受经皮冠脉介入(PCI)治疗时分别使用低分子量肝素(LMWH)和普通肝素(UFH)的疗效和安全性的差异。方法:选择本院2011-01至2012-12接受PCI术患者共200例,根据PCI使用肝素不同分为LMWH组(n=117),UFH组(n=83)。按常规方法,完成PCI术后,根据患者术中靶血管TIMI血流评价各组疗效,根据术中、后72h内出血/血肿、死亡、其他(心包填塞、胸痛、心源性休克、心脏破裂、室间隔穿孔、室速室颤、心脏骤停,阿斯发作、亚急性支架内血栓形成等)不良事件的发生率,比较各组安全性。结果:(1)各组患者临床基线资料差异无统计学意义(P0.05)。(2)各组患者PCI术中支架植入后靶血管血流改变存在统计学差异(P0.05),LMWH在疗效上优于UFH。(3)各组间死亡发生上无统计学差异(P0.05),在出血/血肿及其他(心包填塞、胸痛、心源性休克、心脏破裂、室间隔穿孔、室速室颤、心脏骤停,阿斯发作、亚急性支架内血栓形成等)的发生上存在统计学差异(P0.05),LMWH的不良反应少,安全性更高。结论:LMWH在PCI术中疗效更为显著,且较UFH不良反应少、安全性高,更适用于PCI术的抗凝治疗。     

Interleukin-6 and Asymmetric Dimethylarginine Are Associated with Platelet Activation after Percutaneous Angioplasty with Stent Implantation

Data linking in vivo platelet activation with inflammation and cardiovascular risk factors are scarce. Moreover, the interrelation between endothelial dysfunction as early marker of atherosclerosis and platelet activation has not been studied, so far. We therefore sought to investigate the associations of inflammation, endothelial dysfunction and cardiovascular risk factors with platelet activation and monocyte-platelet aggregate (MPA) formation in 330 patients undergoing angioplasty with stent implantation for atherosclerotic cardiovascular disease. P-selectin expression, activation of glycoprotein IIb/IIIa and MPA formation were determined by flow cytometry. Interleukin (IL)-6, high sensitivity C-reactive protein and asymmetric dimethylarginine (ADMA) were measured by commercially available assays. IL-6 was the only parameter which was independently associated with platelet P-selectin expression and activated GPIIb/IIIa as well as with leukocyte-platelet interaction in multivariate regression analysis (all p<0.05). ADMA was independently associated with GPIIb/IIIa activation (p<0.05). Patients with high IL-6 exhibited a significantly higher expression of P-selectin than patients with low IL-6 (p=0.001), whereas patients with high ADMA levels showed a more pronounced activation of GPIIb/IIIa than patients with low ADMA (p=0.003). In conclusion, IL-6 and ADMA are associated with platelet activation after percutaneous angioplasty with stent implantation. It remains to be established whether they act prothrombotic and atherogenic themselves or are just surrogate markers for atherosclerosis with concomitant platelet activation.     

Synthesis and pharmacology of modified amidine isoxazoline glycoprotein IIb/IIIa receptor antagonists

Selective antagonism of the platelet GPIIb/IIIa receptor represents an attractive mechanism for the prevention and treatment of a number of thrombotic disease states. The antiplatelet activity of the oral GPIIb/IIIa receptor antagonists DMP 754 and DMP 802 have been disclosed. In this paper, the synthesis and biological evaluation of a series of potent N-substituted benzamidine isoxazolines are explored. The effect of benzamidine substitution on the duration of antiplatelet efficacy in dog is presented.     

Novel agents for anti-platelet therapy

Anti-platelet therapy plays an important role in the treatment of patients with thrombotic diseases. The most commonly used anti-platelet drugs, namely, aspirin, ticlopidine, and clopidogrel, are effective in the prevention and treatment of cardio-cerebrovascular diseases. Glycoprotein IIb/IIIa antagonists (e.g., abciximab, eptifibatide and tirofiban) have demonstrated good clinical benefits and safety profiles in decreasing ischemic events in acute coronary syndrome. However, adverse events related to thrombosis or bleeding have been reported in cases of therapy with glycoprotein IIb/IIIa antagonists. Cilostazol is an anti-platelet agent used in the treatment of patients with peripheral ischemia, such as intermittent claudication. Presently, platelet adenosine diphosphate P2Y(12) receptor antagonists (e.g., clopidogrel, prasugrel, cangrelor, and ticagrelor) are being used in clinical settings for their pronounced protective effects. The new protease-activated receptor antagonists, vorapaxar and atopaxar, potentially decrease the risk of ischemic events without significantly increasing the rate of bleeding. Some other new anti-platelet drugs undergoing clinical trials have also been introduced. Indeed, the number of new anti-platelet drugs is increasing. Consequently, the efficacy of these anti-platelet agents in actual patients warrants scrutiny, especially in terms of the hemorrhagic risks. Hopefully, new selective platelet inhibitors with high anti-thrombotic efficiencies and low hemorrhagic side effects can be developed.     

The anti-platelet approach targeting the fibrinogen ligand of the GPIIB/IIIa receptor.

Activation of the platelet surface receptor GPIIb/IIIa is the final pathway of platelet aggregation, regardless of the initiating stimulus. RGD analogues, peptidomimetics and monoclonal antibodies to GPIIb/IIIa have been developed targeting the blockage of the receptor and inhibition of the fibrinogen binding. However, the intrinsic activating effect of GPIIb/IIIa blockers is widely discussed as one potential contributing factor for the disappointing outcome of trials with GPIIb/IIIa inhibitors. An alternative method for thrombus prevention could be the use of specific fibrinogen blockers since they will act at the final step of the platelet aggregation and are expected to leave the receptor unaffected. To achieve this target the design of the fibrinogen ligands could be based on (i) sequences derived from GPIIb/IIIa ligand binding sites, and (ii) sequences complementary to RGD and/or to fibrinogen gamma-chain. The available information, which could be used as a starting point for developing potent fibrinogen ligands, is reviewed.     

Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists

Antagonists of the glycoprotein GPIIb/IIIa are a promising class of antithrombotic agents offering potential advantages over present antiplatelet agents (i.e., aspirin and ticlopidine). Novel tricyclic nonpeptidal GPIIb/IIIa antagonists have been prepared and evaluated in vitro as antagonists of fibrinogen binding to the purified GPIIb/IIIa receptor and as inhibitors of platelet aggregation. The work presented demonstrates the robustness of the benzodiazepinedione (BZDD) scaffold, which can be functionalized at the N¹---C² amide as well as at C⁷, to provide structural diversity and allow optimization of the physiochemical and pharmacological properties of the BZDD based GPIIb/IIIa antagonists. In addition, the resulting new class of tricyclic GPIIb/IIIa antagonists could be used to probe for additional binding interactions on the GPIIb/IIIa receptor and perhaps lead to BZDD based GPIIb/IIIa antagonists with increased potency. The tricyclic molecules reported herein demonstrate that a heterocyclic ring can be fused to the benzodiazepinedione scaffold with retention of anti-aggregatory potency and in the case of tetrazole 30i, increased potency relative to the bicyclic analogue 1c.     

Case-Control Study of Platelet Glycoprotein Receptor Ib and IIb/IIIa Expression in Patients with Acute and Chronic Cerebrovascular Disease

Background

Animal models have been instrumental in defining thrombus formation, including the role of platelet surface glycoprotein (GP) receptors, in acute ischemic stroke (AIS). However, the involvement of GP receptors in human ischemic stroke pathophysiology and their utility as biomarkers for ischemic stroke risk and severity requires elucidation.

Aims

To determine whether platelet GPIb and GPIIb/IIIa receptors are differentially expressed in patients with AIS and chronic cerebrovascular disease (CCD) compared with healthy volunteers (HV) and to identify predictors of GPIb and GPIIb/IIIa expression.

Methods

This was a case—control study of 116 patients with AIS or transient ischemic attack (TIA), 117 patients with CCD, and 104 HV who were enrolled at our University hospital from 2010 to 2013. Blood sampling was performed once in the CCD and HV groups, and at several time points in patients with AIS or TIA. Linear regression and analysis of variance were used to analyze correlations between platelet GPIb and GPIIb/IIIa receptor numbers and demographic and clinical parameters.

Results

GPIb and GPIIb/IIIa receptor numbers did not significantly differ between the AIS, CCD, and HV groups. GPIb receptor expression level correlated significantly with the magnitude of GPIIb/IIIa receptor expression and the neutrophil count. In contrast, GPIIb/IIIa receptor numbers were not associated with peripheral immune-cell sub-population counts. C-reactive protein was an independent predictor of GPIIb/IIIa (not GPIb) receptor numbers.

Conclusions

Platelet GPIb and GPIIb/IIIa receptor numbers did not distinguish between patient or control groups in this study, negating their potential use as a biomarker for predicting stroke risk.     

低分子肝素与普通肝素在介入手术中安全性与疗效的比较

肝素已经普遍用于冠状动脉介入术中,但是由于在应用过程中抗凝效果个体差异大、出血风险相对较高、并发症等问题的日益显现,已经引起了医生们的注意。相对而言,低分子肝素具有抗凝作用强、出血风险低、并发症发生率相对较低、无需实验室监测等优点,进而越来越广泛的在冠状动脉介入术中担当重要角色。普通肝素与低分子肝素在冠状动脉介入术中的有效性与安全性的比较是值得我们去探讨的,知道普通肝素与低分子肝素的优缺点后,可使我们在冠状动脉介入术中更好的选择抗凝药物,使手术的成功率大大提高,降低术后并发症的发生,减轻患者的痛苦。本文结合普通肝素与低分子肝素的药理作用及相关临床研究的结果,分析比较了普通肝素与低分子肝素在冠状动脉介入术中的有效性与安全性。     

Optimal pharmacological therapy in ST-elevation myocardial infarction—a review

Antithrombotic therapy is an essential component in the optimisation of clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. There are currently several intravenous anticoagulant drugs available for primary percutaneous coronary intervention. Dual antiplatelet therapy comprising aspirin and P2Y12 inhibitor represents the cornerstone treatment for STEMI. However, these effective treatment strategies may be associated with bleeding complications. Compared with clopidogrel, prasugrel and ticagrelor are more potent and predictable, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in primary percutaneous coronary intervention. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. In this review, we provide a critical and updated review of currently available antithrombotic therapies used in patients with STEMI undergoing primary PCI. Finding a balance that minimises both thrombotic and bleeding risk is difficult, but crucial. Further randomised trials for this optimal balance are needed.     

Debate: Should the elderly receive thrombolytic therapy, or primary angioplasty, for acute myocardial infarction? The case for primary angioplasty

As the population ages the number of elderly patients presenting with acute myocardial infarction (AMI) will continue to increase. There has been no head-to-head trial of thrombolytic therapy versus primary percutaneous coronary intervention (PCI) in this patient cohort, but there is evidence that favors primary PCI. Most elderly patients are candidates for primary PCI, but many have contraindications to thrombolytic therapy. Hemorrhagic complications are more common in the elderly, and many of these patients present with conditions in which thrombolytic agents have decreased efficacy, such as heart failure or prior bypass surgery. PCI can also obviate the need for further risk stratification in most patients.     

Critical Appraisal of Bivalirudin versus Heparin for Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Trials

Percutaneous coronary intervention with bivalirudin plus bail-out glycoprotein IIb/IIIa inhibitors has been shown to be as effective as unfractionated heparin plus routine glycoprotein IIb/IIIa inhibitors in preventing cardiac ischemic events, but with a lower bleeding risk. It is unknown whether bivalirudin would have the same beneficial effects if compared with heparin when the use of glycoprotein IIb/IIIa inhibitors was similar between treatment arms. We searched the MEDLINE, Web of Science, and Cochrane databases from inception until March 2015 for randomized trials that compared bivalirudin to heparin in patients undergoing percutaneous coronary intervention. We required that the intended use of glycoprotein IIb/IIIa inhibitors was similar between the study groups. Summary estimates were principally constructed by the Peto method. Fifteen trials met our inclusion criteria, which yielded 25,824 patients. Bivalirudin versus heparin was associated with an increased hazard of stent thrombosis (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.15-1.92, P = .002, I² = 16.9%), with a similar hazard of myocardial infarction (OR 1.09, 95% CI 0.98-1.22, P = .11, I² = 35.8%), all-cause mortality (OR 0.88, 95% CI 0.72-1.08, P = .21, I² = 31.5%) and major adverse cardiac events (OR 1.04, 95% CI 0.94-1.14, P = .46, I² = 53.9%). Bivalirudin was associated with a reduced hazard of major bleeding (OR 0.80, 95% CI 0.70-0.92, P = .001, I² = 63.5%). The dose of heparin in the control arm modified this association; when the dose of unfractionated heparin in the control arm was ≥ 100 units/kg, bivalirudin was associated with a reduction in major bleeding (OR 0.55, 95% CI 0.45-0.68, P < .0001), but when the dose of unfractionated heparin was ≤ 75 units/kg, bivalirudin was not associated with reduction in bleeding (OR 1.09, 95% CI 0.91-1.31, P = .36). Among patients undergoing PCI, bivalirudin was associated with an increased hazard of stent thrombosis. Bivalirudin may be associated with a reduced hazard of major bleeding; however, this benefit was no longer apparent when compared with a dose of unfractionated heparin ≤ 75 units/kg.     

Debate: Unstable angina - When should we intervene?

The prognosis of patients who present with non-ST segment elevation acute coronary syndromes (ACS) is guarded. These patients can be risk-stratified on the basis of symptom complex, electrocardiographic ST segment depression, obvious hemodynamic compromise and particularly on the basis of serum troponin level. An elevated troponin level determines risk and also predicts the degree of benefit from treatment with either low molecular weight heparin or platelet glycoprotein (GP) IIb/IIIa blockade. Higher risk patients should undergo early coronary angiography and myocardial revascularization as indicated and feasible. Although studies performed before the advent of coronary stenting and adjunctive platelet GP IIb/IIIa blockade suggested increased hazard for patients undergoing early intervention, recent experience cited herein supports an in-hospital and long-term clinical benefit for the aggressive approach. Here, I propose an algorithm for risk stratification and triage of appropriate patients for adjunctive pharmacotherapy and early revascularization.     

Debate: PCI or CABG for multivessel disease? Viewpoint: No clear winner in an unfair fight

The Arterial Revascularization Therapy Study (ARTS) and the Stent or Surgery (SoS) trial each randomized patients with multivessel disease to either stenting or bypass surgery. The ARTS showed no difference in mortality between the two strategies, other than in diabetic patients, who fared better with surgery. The SoS trial demonstrated increased mortality in the stent arm, a difference that was not attributable to diabetes. Both trials found that the rates of repeat revascularization were lower with surgery, although the rate with stenting was much lower than had been seen in previous trials of angioplasty. Use of antiplatelet therapy such as intravenous glycoprotein IIb/IIIa inhibitors, especially with their pronounced effects in diabetics and in those with multivessel disease, could potentially equalize the playing field or perhaps even tip the balance in favor of percutaneous intervention     

Cation-dependent changes in the binding specificity of the platelet receptor GPIIb/IIIa

The presence of manganese (Mn2+) significantly increases the binding of the platelet surface receptor GPIIb/IIIa to two synthetic peptides Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) and Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (L10) that contain the recognition sequences RGD and KQAGDV, respectively. This results in an increase in the amount of GPIIb/IIIa adsorbed by GRGDSPK- and L10-Sepharose by 12-20-fold. Additionally, Mn2+ eliminates contaminating platelet vitronectin receptor, alpha v beta 3, which copurifies with GPIIb/IIIa on the peptide affinity columns in the absence of Mn2+. In contrast to this increased peptide binding of GPIIb/IIIa, Mn2+ reduces the binding of GPIIb/IIIa to its macromolecular RGD-containing ligands fibrinogen, fibronectin, and vitronectin. These results could mean that Mn2+ changes the structure of the binding site on GPIIb/IIIa such that it is now better suited to accommodate conformations available to the RGD sequence within short, linear synthetic peptides but not available to the RGD sequences within the natural ligands. To support this hypothesis we tested a conformationally restricted cyclic peptide, cyclic 2,10-GPenGHRGDLRCA, which in competition assays, preferentially inhibits the binding of GPIIb/IIIa to fibrinogen but does not inhibit well the binding of other RGD-dependent integrins, alpha v beta 3 and alpha 5 beta 1 to their respective ligands. In such assays, the presence of Mn2+ dramatically changed the binding specificity of GPIIb/IIIa by shifting the preference of the receptor away from the selective peptide, cyclic 2,10-GPen-GHRGDLRCA toward the nonselective GRGDSP peptide. This shift parallels the Mn2(+)-dependent change of the binding of GPIIb/IIIa to its natural protein ligands.     

Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention or after acute coronary syndrome

To prevent recurrent ischaemic events, dual antiplatelet therapy (DAPT) is the standard of care after percutaneous coronary intervention and in the treatment of acute coronary syndrome. Recent evidence supports an adjusted DAPT duration in selected patients.The current paper aims to encourage cardiologists to actively search for patients benefiting from either shorter or prolonged duration DAPT and proposes an algorithm to identify patients who are likely to benefit from such an alternative strategy.Individualised DAPT duration should be considered in high-risk anatomic and/or clinical subgroups or in patients at increased haemorrhagic risk with low ischaemic risk. Both thrombotic and haemorrhagic risk should be assessed in all patients. In patients undergoing percutaneous coronary intervention, the interventional cardiologist could advise on the minimal duration of DAPT. However, in contrast to the minimum duration of DAPT for stent thrombosis prevention, longer duration DAPT is aimed at prevention of spontaneous myocardial infarction, and not at stent thrombosis, and thus the key to success is to treat the patient’s overall thrombotic risk.The advice on the duration of DAPT must be documented in the patient’s records and communicated with the treating physician and general practitioner. DAPT duration should be reassessed at least on a yearly basis.     

C-terminal amino acid determination of the transmembrane subunits of the human platelet fibrinogen receptor, the GPIIb/IIIa complex

Glycoproteins IIb (GPIIb) and IIIa (GPIIIa) form the Ca2(+)-dependent GPIIb/IIIa complex, which acts as the fibrinogen receptor on activated platelets. GPIIb and GPIIIa are synthesized as single peptide chains. The GPIIb precursor is processed proteolytically to yield two disulphide-bonded chains, GPIIb alpha and GPIIb beta. The GPIIb/IIIa complex has two membrane attachment sites located at the C-termini of GPIIb beta and GPIIIa. The short cytoplasmic tails of GPIIb beta and/or GPIIIa become most likely associated to the cytoskeleton of activated platelets. In the present work the C-terminal amino acid residues of platelet GPIIb beta and GPIIIa have been analyzed by protein-chemical methods and compared with those predicted from cDNA analysis. We were able to confirm the positions of the C-termini in both glycoproteins and the identity of the C-terminus predicted for GPIIIa, i.e. threonine. However, glutamine, not glutamic acid as predicted for GPIIb beta from the human erythroleukemic cell line and megakaryocyte cells, was found to be the C-terminal amino acid of GPIIb beta. This indicates that the glutamic acid in the GPIIb precursor is posttranslationally modified to glutamine.