Current Opinion on Endovascular Therapy for Emergent Large Vessel Occlusion Due to Underlying Intracranial Atherosclerotic Stenosis

For recanalization of emergent large vessel occlusions (ELVOs), endovascular therapy (EVT) using newer devices, such as a stent retriever and large-bore catheter, has shown better patient outcomes compared with intravenous recombinant tissue plasminogen activator only. Intracranial atherosclerotic stenosis (ICAS) is a major cause of acute ischemic stroke, the incidence of which is rising worldwide. Thus, it is not rare to encounter underlying ICAS during EVT procedures, particularly in Asian countries. ELVO due to underlying ICAS is often related to EVT procedure failure or complications, which can lead to poor functional recovery. However, information regarding EVT for this type of stroke is lacking because large clinical trials have been largely based on Western populations. In this review, we discuss the unique pathologic basis of ELVO with underlying ICAS, which may complicate EVT procedures. Moreover, we review EVT data for patients with ELVO due to underlying ICAS and suggest an optimal endovascular recanalization strategy based on the existing literature. Finally, we present future perspectives on this subject.

An Assay of Measuring Platelet Reactivity Using Monoclonal Antibody against Activated Platelet Glycoprotein IIb/IIIa in Patients Taking Clopidogrel

BACKGROUND AND OBJECTIVES: Residual platelet reactivity in patients who are taking clopidogrel is commonly measured with VerifyNow assay, which is based on the principle of light transmission aggregometry. However, to evaluate the residual platelet reactivity, it would be more accurate if the reactivity of platelet glycoprotein (GP) IIb/IIIa is directly monitored. In this study, PAC1, a monoclonal antibody against activated platelet GP IIb/IIIa, was used to measure the residual platelet reactivity. SUBJECTS AND METHODS: Twenty seven patients with coronary artery disease taking clopidogrel were enrolled. Platelets in whole blood were stained with fluorescein isothiocyanate (FITC)-conjugated PAC1. Mean fluorescence intensity (MFI) and % positive platelets (PP) were measured with flow cytometry, and the binding index (BI; MFI x %PP/100) was calculated. P2Y12 reaction unit (PRU) and % inhibition of VerifyNow assay were also measured in the usual manner. RESULTS: PRU of VerifyNow assay correlated significantly with MFI, %PP, and BI at 10 microM (r=0.59, 0.73, and 0.60, respectively, all p<0.005) and 20 microM of adenosine diphosphate (ADP; r=0.61, 0.75, and 0.63, respectively, all p<0.005). The % inhibition also correlated significantly with MFI, %PP, and BI at 10 microM (r=-0.60, -0.69, and -0.59, respectively, all p<0.005) and 20 microM of ADP (r=-0.63, -0.71, and -0.62, respectively, all p<0.005). CONCLUSION: Direct measurements of the reactivity of platelet GP IIb/IIIa were feasible using PAC1 and flow cytometry in patients taking clopidogrel. Further clinical studies are required to determine the cut-off values which would define high residual platelet reactivity in patients on this treatment protocol.

Effect of Bivalirudin on Primary Percutaneous Coronary Intervention in Patients With Acute ST-elevation Myocardial Infraction / 中国循环杂志

Objective: To observe the efifcacy and safety of bivalirudin on primary percutaneous coronary intervention (PCI) in patients with acute ST-elevation myocardial infarction (STEMI). Methods: A total of 159 patients with acute STEMI treated by emergent PCI in our hospital from 2011-09 to 2014-01 were retrospectively studied. The patients were divided into 2 groups according to procedural bivalirudin application as Bivalirudin group and Heparin group, and the application of GPI (glycoprotein IIb/IIIa inhibitor) was decided by the operator. The baseline condition, coronary artery imaging condition, peri-operative and 30-day post-operative bleeding, the occurrence rate of MACE were compared between 2 groups. Results: There were 153 patients completed the follow-up study including 72 in Bivalirudin group and 81 in Heparin group. The peri-operative bleeding rates in Bivalirudin group and Heparin group were 6.5% vs 11.0%, the in-stent thrombosis rates were 0% vs 1.2%, 30-day post-operative bleeding rates were 9.7% vs 13.5% and the occurrence of MACE were 1.4% vs 7.4% allP>0.05. Conclusion: THE application of bivalirudin in emergent PCI is safe and effective in patients with acute STEMI, it has certain trend to reduce bleeding in relevant patients.

Safety and Efficacy Comparison of Platelet Glycoprotein IIb/IIIa Antagonist in Treating STEMI Patients by Intracoronary-intravenous Administration and Intravenous Administration:A Meta-analysis / 中国循环杂志

Objective: To compare the safety and efifcacy of platelet glycoprotein IIb/IIIa antagonist in treating STEMI patients by intracoronary-intravenous administration and intravenous administration. Methods: We searched PubMed, Embase, Cochrane library, CNKI, VIPH and Wanfang database, the retrieval stopped at 2014-03. According to 5.0.2 Cochrane handbook, 2 scientists collected 2494 STEMI patients treated by IIb/IIIa antagonist from 20 references, and they were divided into 2 groups. Combination group, the patients received intracoronary, then intravenous administration, n=1258 and Intravenous group, the patients receive only intravenous administration, n=1236. RevMan 5.0 software was used for Meta-analysis. Results: At 1 month after PCI treatment, compared with Intravenous group, the Combination group had better conditions of TIMI 3, TMP 3, ST segment recovery, MACE occurrence and MI area changes, all P0.05. Conclusion: Intracoronary-intravenous administration of platelet glycoprotein IIb/IIIa antagonist had the better effect for treating STEMI patients without increasing the side effects of post-operative bleeding and thrombocytopenia.

Consecutive Multivessel Myocardial Infarction during Primary Percutaneous Coronary Intervention / 대한내과학회지

ST-elevation myocardial infarction (STEMI) involving multivessel coronary arteries is extremely rare. Consecutive STEMI in a nonculprit vessel during primary percutaneous coronary intervention (PCI) of the culprit vessel has not been reported. A 53-year-old male presented to the emergency department with anterior wall STEMI. Just after successful primary PCI of the left anterior descending artery, inferior wall STEMI developed. PCI of the right coronary arteries was performed successfully. Five days later, the patient was discharged without symptoms of heart failure. This case underlines the high thrombogenicity along the coronary arteries in patients with STEMI.

Current status of glycoprotein IIB/IIIA receptor antagonists and evaluation of their molecular modeling.

Abciximab, Eptifibatide and Tirofiban are the three main glycoprotein IIb/IIIa receptor antagonists which have played a vital role in the field of cardiac medicine. They work by blocking the final mechanism of platelet aggregation pathway. These antagonists are widely used in treating acute coronary syndrome, myocardial infarction and during percutaneous coronary intervention (PCI). In this review, we have examined the chemistry, mechanism of action and clinical uses of these glycoprotein IIb/IIIa receptor antagonists. We also tried to study the binding mode of both eptifibatide and tirofiban with the glycoprotein IIb/IIIa receptors using molecular docking software. It appears that blocking the ASP 224 may be the cause for platelet activity inhibition.

EDTA Inhibits the Binding of Clone 96.2C1, an Anti-CD41a Monoclonal Antibody, to the Platelets and Addition of Heparin and CaCl2 to the Antibody Neutralizes the EDTA-induced Inhibitory Effect

BACKGROUND: The binding of some monoclonal antibodies platelet glycoprotein (GP) IIb/IIIa, which is frequently used for flow cytometric immnophenotyping, is known to be inhibited by EDTA. To select the ideal antibodies to be included in the 'Acute Leukemia Panel' for immunophenotyping of acute leukemia, we compared the inhibitory effect of EDTA on the binding of 5 different clones of monoclonal antibodies to platelet GP IIb/IIIa. We also discovered a simple method to neutralize this inhibitory effect. METHODS: Flow cytometric measurement of the number of platelet GP IIb/IIIa binding sites with different anticoagulants was performed using a panel of 5 clones of monoclonal antibodies against CD41 (clone PM6/248), CD41a (clone 96.2C1 & clone HIP8), CD41b (clone HIP2) and CD61 (clone VI-PL2), and the results are expressed as the mean equivalent soluble fluorochrome (MESF) values. RESULTS: The MESF value of the EDTA platelets stained with anti-CD41a, clone 96.2C1 antibody showed a significantly lower value than the MESF of platelets anticoagulated with heparin or citrate (P<0.001). The inhibitory effect of EDTA on the binding of anti-CD41a, clone 96.2C1 antibody to the platelets was neutralized by addition of heparin and CaCl2. The mean MESF value of EDTA platelets stained with anti-CD41a, clone 96.2C1 antibody was significantly increased by the addition of heparin and CaCl2 (P=0.0001). CONCLUSION: The false-negative results of the binding of anti-CD41a, clone 96.2C1 antibody to the platelets seem to be due to the calcium chelating property of EDTA, and the addition of CaCl2 and heparin could be used as an easy compensatory measure for the inhibitory effect of EDTA on other antibodies as well.

Rescue Use of Tirofiban for Acute Carotid In-Stent Thrombosis

Carotid artery stenting is widely performed for extracranial carotid artery stenosis. In-stent thrombosis is a rare but potentially devastating complication. We present a case of acute in-stent thrombosis immediately following stent insertion and post-balloon dilatation in a 64-year-old male. Thrombosis was successfully treated by intravenous tirofiban, a glycoprotein IIb/IIIa receptor inhibitor.

Rescue Treatment with Intra-arterial Tirofiban Infusion and Emergent Carotid Stenting

Rapid arterial rethrombosis is associated with high-grade residual stenosis and usually occurs at the site of the initial occlusion, resulting in reocclusion of the recanalized artery. Platelets may play an active role in such rethrombosis after thrombolytic-induced clot lysis. Given that glycoprotein IIb/IIIa receptor blockers, like tirofiban, prevent thrombus formation by inhibiting the final common pathway of platelet aggregation, they may be helpful for treating rethrombosis after thrombolysis. A 64-year-old man presented with an acute ischemic stroke due to internal carotid artery (ICA) occlusion. The ICA was recanalized by intravenous thrombolysis but reoccluded shortly after recanalization. The reoccluded ICA was successfully recanalized using intra-arterial tirofiban. A carotid stent was subsequently inserted to relieve severe stenosis and to prevent recurrent stroke. Here, we report a case of rescue treatment of a successfully recanalized ICA by intra- arterial tirofiban. We suggest that rescue use of intra-arterial tirofiban may be effective and safe, especially in hemorrhage prone situations, due to the relatively lower dose of tirofiban compared with intravenous doses.

Antiplatelet Agents in High-Risk Patients with Coronary Artery Disease

The role of platelets is well known in the atherogenesis, acute coronary syndrome and development of complications of percutaneous coronary intervention. Until recently, aspirin was the only antiplatelet agent available for the primary and secondary prevention of coronary heart disease. Over the past several years, there has been a substantial expansion in our antiplatelet armamentarium, as well as in our understanding of the clinical importance of antiplatelet therapy in patients with coronary artery disease. The benefits and limitations of the currently available antiplatelet agents, including aspirin, thienopyridines (ticlopidine and clopidogrel) and the platelet glycoprotein IIb/IIIa blockers, in the secondary prevention of coronary heart disease, and high-risk clinical situations, such as unstable angina, acute myocardial infarction and percutaneous coronary intervention, have been reported. Antiplatelet agents should be used, in proper combination, in all relevant cases, as they have been shown to improve the prognosis of various forms of high-risk patients with coronary artery disease.

The inhibitory effect of platelet glycoprotein IIb/IIIa receptor blocker-coated stent on porcine coronary stent restenosis / 대한내과학회지

BACKGROUND: The problems of coronary stent thrombosis and restenosis still remain to be solved.The glycoprotein IIb/IIIa receptor blocker, Abciximab (ReoPro), plays important roles in the treatment of high-risk patient with acute platelet-rich thrombus and in the inhibition of smooth muscle cell proliferation. The aim of this study was to determine whether the use of ReoPro-coated stents could reduce the neointimal formation in a porcine coronary stent restenosis model. METHODS: ReoPro was coated on the surface of stent by means of plasma polymerization followed by chemical grafting. Stent overdilation injury was performed with control bare stent (Group I, n=13), and ReoPro-coated stents (Group II, n=14). Follow-up quantitative coronary angiogram was performed at 4 weeks after stenting and histopathologic assessment were compared in both groups. RESULTS: The diameter stenosis by QCA between two groups was significantly higher in Group I (23+/-5 % vs. 15+/-7 %, p=0.003). On histopathologic examination, no in-stent thrombus was observed. The percent area stenosis was significantly higher in Group I than in Group II (48+/-17 % vs. 30+/-16 %, p=0.01). The area of neoinima was larger in Group I than in Group II (3.2+/-1.2 mm2 vs. 2.0+/-1.0 mm2, p=0.01). By immunocytochemistry, proliferation cell nuclear antigen indices were higher in Group I (4.2+/-2.1 %, vs 2.4+/-1.8 % p=0.03). CONCLUSION: The ReoPro-coated stent is safe and effective in the prevention of in-stent thrombus and restenosis, which may be related with the inhibition of platelet thrombus and neointimal cell proliferation.

Study of Autoantibodies Against Platelet GP IIb/IIIa and GP Ib/IX in Childhood Chronic Idiopathic Thrombocytopenic Purpura

PURPOSE: Chronic idiopathic thrombocytopenic purpura (CITP) is an autoimmune disease caused by autoantibodies reacting to certain antigens, and platelet glycoprotein (GP) IIb/IIIa and GP Ib/IX complexes are thought to be some of those antigens. However, the clinical significance of anti-GP autoantibodies in CITP patients is unknown. In this study, we investigated the clinical correlation between the presence of circulating autoantibodies against GP IIb/IIIa and GP Ib/IX, and disease activity. MEHTODS: From December 1997 to June 1998, 20 CITP patients were enrolled in this study. Autoantibodies against GP IIb/IIIa and GP Ib/IX in patient's sera during treatment were detected by immunoblotting, and their platelet counts at the initial evaluation and 6 month follow-up were compared according to the presence or the absence of antibodies. RESULTS: Autoantibodies to GP antigens were found in 40% (8/20) of the patients. Seven patients were positive for GP IIb/IIIa; 4 for GP Ib/IX and 3 for both. GP autoantibody-positive patients had lower mean platelet counts than GP autoantibody-negative patients at initial evaluation (133,000/microliter vs 172,000/microliter, P>0.05) and at 6 month follow-up (154,000/microliter vs 192,000/microliter, P>0.05). Detection of GP autoantibodies related more with active disease than with remission at initial evaluation (45.5%(5/11) vs 33.3%(3/9), P>0.05) and at 6 month follow-up (50.0%(5/10) vs 30.0% (3/10), P>0.05). There was no detection of GP-specific antibodies in 3 splenectomized patients. CONCLUSION: It is hard to conclude on our data alone that the presence of GP autoantibodies correlates with disease status in CITP, although it seems to associate with lower platelet counts.

Study of Autoantibodies Against Platelet GP IIb/IIIa and GP Ib/IX in Childhood Chronic Idiopathic Thrombocytopenic Purpura

PURPOSE: Chronic idiopathic thrombocytopenic purpura (CITP) is an autoimmune disease caused by autoantibodies reacting to certain antigens, and platelet glycoprotein (GP) IIb/IIIa and GP Ib/IX complexes are thought to be some of those antigens. However, the clinical significance of anti-GP autoantibodies in CITP patients is unknown. In this study, we investigated the clinical correlation between the presence of circulating autoantibodies against GP IIb/IIIa and GP Ib/IX, and disease activity. MEHTODS: From December 1997 to June 1998, 20 CITP patients were enrolled in this study. Autoantibodies against GP IIb/IIIa and GP Ib/IX in patient's sera during treatment were detected by immunoblotting, and their platelet counts at the initial evaluation and 6 month follow-up were compared according to the presence or the absence of antibodies. RESULTS: Autoantibodies to GP antigens were found in 40% (8/20) of the patients. Seven patients were positive for GP IIb/IIIa; 4 for GP Ib/IX and 3 for both. GP autoantibody-positive patients had lower mean platelet counts than GP autoantibody-negative patients at initial evaluation (133,000/microliter vs 172,000/microliter, P>0.05) and at 6 month follow-up (154,000/microliter vs 192,000/microliter, P>0.05). Detection of GP autoantibodies related more with active disease than with remission at initial evaluation (45.5%(5/11) vs 33.3%(3/9), P>0.05) and at 6 month follow-up (50.0%(5/10) vs 30.0% (3/10), P>0.05). There was no detection of GP-specific antibodies in 3 splenectomized patients. CONCLUSION: It is hard to conclude on our data alone that the presence of GP autoantibodies correlates with disease status in CITP, although it seems to associate with lower platelet counts.

Increased Activation of Platelet Glycoprotein IIb/IIIa in Hypercholesterolemic Patients

BACKGROUND: Platelet function is directly influenced by lipoproteins, and platelets from hypercholesterolemic patients display increased reactivity which is related to initiation, progression, and development of thromboembolic complications in atherosclerosis. But the exact mechanism of this effect is unclear. METHODS: In this study, total and activated numbers of platelet glycoprotein (Gp) IIb/IIIa were evaluated in twenty patients (7 men; age, 55.4+/-8.7 years) with hypercholesterolemia (plasma total cholesterol level over 240 mg/dL and normal triglyceride level) and twenty one subjects (8 men; 51.1+/-13.7 years) with normal plasma cholesterol and triglyceride levels. Flow cytometry was used to detect the binding of fluorescein isothiocyanate (FITC)-conjugated anti-CD41 or PAC1 to platelet Gp IIb/IIIa in whole blood. When whole blood was incubated with PAC1, platelets were also activated with adenosine diphosphate (ADP) or thrombin. RESULTS: PAC1 was more bound to unstimulated platelets from patients with hypercholesterolemia (p<0.005), and binding of PAC1 correlated significantly with plasma total cholesteol (r=0.48, p=0.002) and LDL-cholesterol (r=0.47, p=0.002) levels. Binding of PAC1 to unstimulated platelets increased as binding of anti-CD41 increased (r=0.40, p=0.01). On multivariate linear regression analysis, plasma total cholesterol level and binding of anti-CD41 were independent variables that determined binding of PAC1. After ADP- or thrombin-stimulation, binding of PAC1 to platelets and percentage of antibody positive cells were also greater in patients with hypercholesterolemia (p<0.05). There was a significant positive correlation between mean platelet volume and binding of anti-CD41 to unstimulated platelets (r=0.46, p<0.0050), but the latter was not different between hypercholesterolemia and control groups. CONCLUSION: Unstimulated platelets from patients with hypercholesterolemia had similar total number of Gp IIb/IIIa to those from control subjects, but had more activated Gp IIb/IIIa. After ADP- or thrombin-stimulation, platelet Gp IIb/IIIa was also more activated under hypercholesterolemia.