Evidence for the use of glycoprotein IIb/IIIa inhibitors (GPIs) in the management of acute coronary syndrome (ACS) is from the era of either limited utilization of P2Y12 inhibitors or prior the introduction of more potent P2Y12 inhibitors. This leads to divergent opinions regarding the role of these agents in contemporary practice. This study sought the opinion of cardiovascular clinical pharmacists regarding the role of GPIs in the modern of ACS management. A 13-question survey was created and distributed from June 2018 to July 2018 via the American College of Clinical Pharmacy's Cardiology Practice and Research Network e-mail listserv. The survey consisted of questions regarding the ideal use of GPIs in ACS management, preferred agent selection, and rational for selection. All results were analyzed with descriptive statistics. There were a total 69 responses of 1175 (response rate 5.9%). The majority felt there was still a role for GPI in accordance to the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for ST-segment elevation myocardial infarction (65.2%), with eptifibatide being preferred (55.1%). For non-ST-segment myocardial infraction (NSTEMI), only 49.3% felt role of GPI was in line with the ACC/AHA guidelines, but a notable number of respondents felt GPIs were only indicated in NSTEMI patients for bailout or thrombotic complications (18.8%). A majority (56.5%) felt GPIs could be used as an alternative for cangrelor when bridging. The decision to use one agent over another were efficacy data, cost, and pharmacokinetic profile.

In addition to hemostasis, human platelets have several immune functions and interact with infectious pathogens including HIV in vitro. Here, we report that platelets from HIV-infected individuals on combined antiretroviral drug therapy (ART) with low blood CD4+ T cell counts (<350 cells/μl) contained replication-competent HIV despite viral suppression. In vitro, human platelets harboring HIV propagated the virus to macrophages, a process that could be prevented with the biologic abciximab, an anti-integrin αIIb/β3 Fab. Furthermore, in our cohort, 88% of HIV-infected individuals on ART with viral suppression and with platelets containing HIV were poor immunological responders with CD4+ T cell counts remaining below <350 cells/μl for more than one year. Our study suggests that platelets may be transient carriers of HIV and may provide an alternative pathway for HIV dissemination in HIV-infected individuals on ART with viral suppression and poor CD4+ T cell recovery.

Platelets are responsible for the formation of thrombus after endothelial injury, which is vital in maintaining normal hemostasis. Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors prevent platelet aggregation by blocking glycoprotein IIb/IIIa receptors; thus they found application in the management of coronary artery disease (CAD). The available GP IIb/IIIa inhibitors include abciximab, tirofiban, and eptifibatide. These agents, along with aspirin, are used in patients with unstable angina with PCI within 24 hrs. Among them, abciximab is a monoclonal antibody receptor inhibitor, and the other two are non-antibody receptor inhibitors. The Food and Drug Administration (FDA) had approved GP IIb/IIIa inhibitors for the management of acute coronary syndromes (ACS) such as unstable angina and non-ST elevation myocardial infarction requiring percutaneous coronary interventions (PCI) within 24 hrs. GP IIb/IIIa inhibitors were the drug of choice in ACS patients during the plain balloon angioplasty era when complications secondary to post-procedure acute thrombosis were frequent.[1] However, after the introduction of oral P2Y12 inhibitors, the role of GP IIb/IIIa inhibitors in ACS is decreased. Currently, American College of Cardiology/American Heart Association has recommends the use of GP IIb/IIIa inhibitors in ACS when patient is allergic or cannot tolerate to P2Y12 inhibitors (Class I) or in patients who are undergoing PCI has received P2Y12 inhibitors but at higher risk for thrombus and in those who are allergic to aspirin (Class IIa). Before the advent of stents and the use of dual antiplatelets, a prolonged infusion (12 to 24 hours) of GP IIb/IIIa inhibitor was the recommendation for ACS patients. However, currently, a short duration infusion or bolus only methods are recommended to avoid bleeding complications.[2][3][4] Intracoronary infusion of GP IIb/IIIa inhibitors in multiple trials had shown improvement in epicardial and myocardial perfusion with fewer adverse events. However, clinical trials did not find a significant improvement in outcomes or recurrent MI. In a major trial, AIDA-STEMI involving 2065 patients, researchers studied intracoronary infusion of abciximab, but there was no difference in the primary endpoint of death and new MI.[5] Currently, the use of intracoronary GP IIb/IIIa inhibitors is a Class II b recommendation in PCI during STEMI.[6]

Acute coronary syndrome (ACS) patients with diabetes have significantly worse cardiovascular outcomes than those without diabetes. This study aimed to compare the performance of The Thrombolysis In Myocardial Infarction (TIMI), Global Registry of Acute Coronary Events (GRACE), Primary Angioplasty in Myocardial Infarction (PAMI), and Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) risk scores in predicting long-term cardiovascular outcomes in diabetic patients with ST-segment elevation myocardial infarction (STEMI). From the Acute Coronary Syndrome-Diabetes Mellitus Registry of the Taiwan Society of Cardiology, patients with STEMI were included. The TIMI, GRACE, PAMI, and CADILLAC risk scores were calculated. The discriminative potential of risk scores was analyzed using the area under the receiver-operating characteristics curve (AUC). In the 455 patients included, all four risk score systems demonstrated predictive accuracy for 6-, 12- and 24-month mortality with AUC values of 0.67-0.82. The CADILLAC score had the best discriminative accuracy, with an AUC of 0.8207 (p<0.0001), 0.8210 (p<0.0001), and 0.8192 (p<0.0001) for 6-, 12-, and 24-month mortality, respectively. It also had the best predictive value for bleeding and acute renal failure, with an AUC of 0.7919 (p<0.05) and 0.9764 (p<0.0001), respectively. Patients with CADILLAC risk scores >8 had poorer 2-year survival than those with lower scores (log-rank p<0.0001). In conclusion, the CADILLAC risk score is more effective than other risk scores in predicting 6-month, 1-year, and 2-year all-cause mortality in diabetic patients with STEMI. It also had the best predictive value for in-hospital bleeding and acute renal failure.

Knowledge of platelet count and function is key to ensuring appropriate hemostatic management. We hypothesized that the novel, portable TEG®6s coagulation assessment system could evaluate the contribution of both platelet count and function to clot formation. Whole-blood samples with variable platelet counts were prepared from healthy volunteers. Platelet function was adjusted using seven concentrations of abciximab and evaluated by light transmission aggregometry (LTA) with TRAP agonist. Maximum amplitude (MA), reaction time (R) and activated clotting time (ACT) were assessed in citrated kaolin (CK), CK with heparinase (CKH), citrated RapidTEG® (CRT), and citrated functional fibrinogen (CFF) assays. Positive correlations were observed between platelet count and CK.MA, CKH.MA, and CRT.MA (p < .0001), and CK.R, CKH.R, and CRT.ACT (p < .05). Platelet count could be accurately quantified in the range 28-91 k/μL, 28-86 k/μL and 28-74 k/μL for CK.MA, CKH.MA, and CRT.MA, respectively. CK.MA, CKH.MA, and CRT.MA showed significant negative relationships with abciximab concentration (p < .001). Platelet function inhibition was detected by all three assays at >68% measured by LTA and quantified in the range 68.4-82% (CK), 69.4-88% (CKH), and 69.7-76% (CRT). This demonstrates the TEG®6s analyzer can accurately evaluate platelet count and function at the site-of-care.

Life-threatening thrombocytopenia and bleeding, common side effects of clinically available αIIbβ3 antagonists, are associated with the induction of ligand-induced integrin conformational changes and exposure of ligand-induced binding sites (LIBSs). To address this issue, we examined intrinsic mechanisms and structure-activity relationships of purified disintegrins, from Protobothrops flavoviridis venom (i.e., Trimeresurus flavoviridis), TFV-1 and TFV-3 with distinctly different pro-hemorrhagic tendencies. TFV-1 with a different αIIbβ3 binding epitope from that of TFV-3 and chimeric 7 × 103 Fab, i.e., Abciximab, decelerates αIIbβ3 ligation without causing a conformational change in αIIbβ3, as determined with the LIBS antibody, AP5, and the mimetic, drug-dependent antibody (DDAb), AP2, an inhibitory monoclonal antibody raised against αIIbβ3. Consistent with their different binding epitopes, a combination of TFV-1 and AP2 did not induce FcγRIIa-mediated activation of the ITAM-Syk-PLCγ2 pathway and platelet aggregation, in contrast to the clinical antithrombotics, abciximab, eptifibatide, and disintegrin TFV-3. Furthermore, TFV-1 selectively inhibits Gα13-mediated platelet aggregation without affecting talin-driven clot firmness, which is responsible for physiological hemostatic processes. At equally efficacious antithrombotic dosages, TFV-1 caused neither severe thrombocytopenia nor bleeding in FcγRIIa-transgenic mice. Likewise, it did not induce hypocoagulation in human whole blood in the rotational thromboelastometry (ROTEM) assay used in perioperative situations. In contrast, TFV-3 and eptifibatide exhibited all of these hemostatic effects. Thus, the αIIbβ3 antagonist, TFV-1, efficaciously prevents arterial thrombosis without adversely affecting hemostasis.

A case is described in which the short-acting glycoprotein IIb/IIIa receptor antagonist tirofiban was used in combination with heparin, aspirin and prasugrel to successfully treat extensive intracoronary thrombus in a delayed presentation STEMI, illustrating the utility of this approach.

Intermediate (CD14++CD16+) monocytes have important pro-inflammatory and atherogenic features and are increased in patients with chronic kidney disease (CKD). The present study aims to elucidate the role of the uremic milieu and of platelet activation in monocyte differentiation. Monocyte subtypes were analyzed in CKD patients (n = 193) and healthy controls (n = 27). Blood from healthy controls (Ctrl; n = 8) and hemodialysis patients (HD; n = 8) was centrifuged, and plasma (pl) was exchanged between Ctrl and HD (Ctrlcells/HDpl and HDcells/Ctrlpl) or reconstituted as original (Ctrlsham and HDsham) and incubated for 24 h (T24). Monocyte differentiation and platelet aggregation to monocytes (MPA) was assessed by flow cytometry. Especially, a higher proportion of CD14++CD16+ monocytes was found in hemodialysis (HD) patients (p < 0.01). In plasma exchange experiments, Ctrl cells/HD pl T24 showed an increased percentage of CD14++CD16+ monocytes versus Ctrl sham (33.7% ± 15 vs. 15.7% ± 9.6; P < 0.005), comparable to the level of CD14++CD16+ monocytes in the HD sham condition. The percentage of CD14++CD16+ monocytes was lowered by suspending HD cells in Ctrl pl (18.4% ± 7.8 vs. 36.7% ± 15 in HD sham; P < 0.005) reaching the level of the Ctrl sham condition (15.7% ± 9.6). A mixture of uremic sulfates increased CD14++CD16+ monocytes compared to control (19.8 ± 9.6% vs. 15.8 ± 10.9%; P < 0.05), paralleled by a rise MPA. Blocking MPA by abciximab, a potential therapeutic strategy, or anti-CD62P did not inhibit differentiation towards the CD14++CD16+ monocytes. In conclusion, in the present cohort, CD14++CD16+ monocytes are especially increased in HD patients and this can at least in part be attributed to the presence of the uremic milieu, with uremic sulfates inducing a reversible shift towards pro-inflammatory CD14++CD16+ monocytes.

Monoclonal antibody (mAb) drugs offer a number of valuable treatments. Many newly developed mAb drugs include artificial modification of amino acid sequences from human origin, which may cause higher immunogenicity to induce anti-drug antibodies (ADA). If the immunogenicity of a new candidate can be understood in the nonclinical phase, clinical studies will be safer and the success rate of development improved. Empirically, in vitro immunogenicity assays with human cells have proved to be sufficiently sensitive to nonhuman proteins, but not to human/humanized mAb. To detect the weaker immunogenicity of human-based mAb, a more sensitive biomarker for in vitro assays is needed. The in vitro study here developed a proliferation assay (TH cell assay) using flow cytometry analysis that can detect a slight increase in proliferating TH cells. Samples from 218 donors treated with a low-immunogenic drug (etanercept) were measured to determine a positive threshold level. With this threshold, positive donor percentages among PBMC after treatment with higher-immunogenicity mAb drugs were noted, that is, 39.5% with humanized anti-human A33 antibody (hA33), 27.3% with abciximab, 25.9% with adalimumab, and 14.8% with infliximab. Biotherapeutics with low immunogenicity yielded values of 0% for basiliximab and 3.7% for etanercept. These data showed a good comparability with previously reported incidences of clinical ADA with the evaluated drugs. Calculations based on the data here showed that a TH cell assay with 40 donors could provide statistically significant differences when comparing low- (etanercept) versus highly immunogenic mAb (except for infliximab). Based on the outcomes here, for screening purposes, a practical cutoff point of 3/20 positives with 20 donors was proposed to alert immunogenicity of mAb drug candidates.

The role of glycoprotein IIb/IIIa inhibitors (GPI) in primary percutaneous coronary intervention (PPCI) remains uncertain. Previous analyses compare PPCI outcomes with clopidogrel plus GPI, versus without GPI. This does not reflect modern contemporary PPCI practice with ticagrelor or prasugrel. Nor does it answer the important question faced daily by PPCI operators: should GPI be used routinely or selectively? We aim to determine whether a strategy of routine use of GPI in contemporary PPCI practice is superior to selective GPI use. A total of 110,327 consecutive PPCIs performed in England were prospectively recorded in the British Cardiovascular Intervention Society Database (2009 to 2015). The cohort was divided into routine and selective GPI usage groups based on the PPCI operator's strategy, defined as GPI used in >75% and <25% PPCIs, respectively. Overall, GPI use declined from 73.1% to 43.3% of PPCIs. Routine compared with selective GPI usage was associated with lower all-cause 1-year mortality: 9.7% versus 11.0%, p < 0.001. There was a consistent survival benefit for routine GPI usage as compared with selective GPI usage: univariable analysis (hazard ratio = 0.88 [95% confidence interval 0.83 to 0.93], p < 0.001), multivariable analysis (hazard ratio = 0.82 [0.77 to 0.88], p < 0.001). For survival, there was no interaction between GPI usage and the type of P2Y12-inhibitor used. In conclusion, a strategy of routine GPI usage in patients who underwent PPCI was associated with lower all-cause mortality as compared with selective GPI usage. This benefit was maintained despite 44.3% of patients receiving prasugrel or ticagrelor.

This article reviews the major pharmacologic features of, and clinical evidence on, adjuvant medical therapy in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. These drugs include oral antiplatelets (aspirin and P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor), intravenous antiplatelet agents (the P2Y12 inhibitor cangrelor, GP IIb/IIIa inhibitors such as abciximab, eptifibatide and tirofiban), and intravenous anticoagulant agents (unfractionated heparin, low molecular weight heparin and bivalirudin).

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.