Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo

Platelet-mediated thrombus formation at the site of vascular injury is a major trigger for thrombo-ischemic complications after coronary interventions. The platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in the initiation of arterial thrombus formation. Endothelial denudation of the right carotid artery in rabbits was induced through balloon injury. Subsequently, local delivery of soluble, dimeric fusion protein of GPVI (GPVI-Fc) (n = 7) or control Fc (n = 7) at the site of vascular injury was performed with a modified double-balloon drug-delivery catheter. Thrombus area within the injured carotid artery was quantified using a computer-assisted image analysis and was used as index of thrombus formation. The extent of thrombus formation was significantly reduced in GPVI-Fc- compared with control Fc-treated carotid arteries (relative thrombus area, GPVI-Fc vs. Fc: 9.3 +/- 4.2 vs. 2.3 +/- 1.7, p < 0.001). Local delivery of soluble GPVI resulted in reduced thrombus formation after catheter-induced vascular injury. These data suggest a selective pharmacological modulation of GPVI-collagen interactions to be important for controlling onset and progression of pathological arterial thrombosis, predominantly or even exclusively at sites of injured carotid arteries in the absence of systemic platelet therapy.     

Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy

Introduction

Currently, there is an intense debate about whether comedication with proton pump inhibitors (PPIs) weakens the antiplatelet effect of clopidogrel in patients undergoing coronary stent implantation. Competing mechanisms on the hepatic cytochrome 2C19 level are proposed. The aim of this study was to assess the impact of PPI treatment on clopidogrel response by measuring the ex vivo platelet aggregation in patients with coronary intervention.

Methods

1425 consecutive patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention were enrolled in this single centre study. PPI comedication was defined as PPI intake ≥ 1 week prior to a 600 mg clopidogrel loading dose. PPI treatment was based on physician preference. Residual platelet aggregation (RPA) was measured by optical aggregometry. To correct for potential selection bias, propensity score matching was applied.

Results

RPA was significantly higher in PPI-treated patients compared with non-PPI-users (final aggregation 34.0% vs. 29.8%, p < 0.001). Low responder defined as RPA in the upper tertile were more often found in PPI-users. After adjustment for relevant confounders, PPI treatment was independently associated with higher RPA-levels.

Discussion

We demonstrated that peri-procedural co-administration of PPIs significantly decreases the effect of clopidogrel on RPA. To assess if clopidogrel-PPI interaction results in a higher susceptibility for cardiovascular events remains subject to further investigations.     

Variable response to clopidogrel in patients with coronary artery disease

Antiplatelet drug resistance is a multifactorial phenomenon that affects a large number of cardiovascular patients with symptomatic coronary artery disease. Although unique definitions for aspirin and clopidogrel resistance are missing, there is growing evidence for a clinical importance of response to antiplatelet therapy. The prevalence for aspirin and clopidogrel resistance has been reported to be between 5 and 30% in literature. Moreover, recent data suggest a high rate of dual antiplatelet drug resistance. Although there are convincing data about an association of aspirin resistance and clinical outcome, little is known about the clinical relevance of clopidogrel hyporesponsiveness. This article reviews the evidence for the clinical impact of antiplatelet drug resistance, with particular attention on the clinical outcome of clopidogrel low response according to current clinical data. Additional systematic studies are needed to evaluate the effects of alternative antiplatelet therapies in patients identified as low responders.     

Platelet-leukocyte interactions in inflammation and atherothrombosis

Inflammatory processes at the vascular wall result in the development of atherosclerosis. Platelet interactions with leukocytes may play a key role in the initiation of inflammation. They trigger autocrine and paracrine activation processes, leading to leukocyte recruitment (in)to the vascular wall. This article highlights the molecular basis and the inflammatory pathways initiated by platelet-leukocyte interactions.     

Platelets and stromal cell-derived factor-1 in progenitor cell recruitment

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that binds to its sole counterreceptor, CXCR4. It is well reported that the SDF-1/CXCR4 signaling pathway is of vital importance to human development and to various pathophysiological phenomena, including hematopoiesis, angiogenesis, atherosclerosis, cancer growth, metastasis, and human immunodeficiency virus infection. SDF-1 promotes mobilization of bone marrow-derived endothelial progenitor cells (EPCs) to the circulation in response to vascular injury. Recently, we found that platelets express and release SDF-1 into the microcirculation upon activation and we observed that platelet-derived SDF-1 is functionally involved in recruitment of EPCs to arterial thrombi in vivo. This review discusses the unique functions of this chemokine and the newly discovered impact of platelet-derived SDF-1 into the recruitment of progenitor cells to vascular injury areas, and its subsequent effects in atherosclerosis, vascular repair, and angiogenesis.     

Inhibition of foam cell formation using a soluble CD68-Fc fusion protein

The appearance of lipid-rich foam cells is a major feature of vulnerable atherosclerotic plaque formation. The transformation of macrophages into foam cells results from excessive uptake of cholesterol-rich particles by scavenger receptors such as CD68. We cloned a CD68-Fc immunoadhesin, a fusion protein consisting of the extracellular domain of the human CD68 and a human Fc domain, and investigated the function in vitro. Specific binding of CD68-Fc to OxLDL with an affinity of 10 nmol/L was determined by surface plasmon resonance and increased binding to lipid-rich human and ApoE^?/? mice plaque tissue. This was confirmed both by immunohistochemical staining of CD68-Fc-treated paraffin sections from human plaques and by ELISA-based quantification of CD68-Fc binding to human atherosclerotic plaque extracts. In an in vitro model of macrophage/foam cell formation, CD68-Fc reduced foam cell formation significantly. This was caused both by interference of CD68-Fc with OxLDL uptake into macrophages and platelets and by the inhibition of platelet/OxLDL phagocytosis. Finally, expression of metalloproteinases by macrophages/foam cells was inhibited by CD68-Fc. In conclusion, CD68-Fc seems to be a promising new tool for preventing macrophage/foam cell formation. Thus, CD68-Fc might offer a novel therapeutic strategy for patients with acute coronary syndrome by modulating the generation of vulnerable plaques.     

The role of platelets for the pathophysiology of acute coronary syndromes

Cardiovascular diseases, especially ischaemic heart disease, are actually the most frequent causes of death in the Western world and represent a central challenge for modern research and medicine. The pathophysiology of ischaemic heart disease is based upon the development and biological remodelling of atherosclerotic plaques. Mainly at late stages, but also in the early phase of atherosclerosis, rupture of the atherosclerotic plaque occurs and may lead to the clinical manifestation of acute coronary syndromes, including unstable angina pectoris, non-transmural or transmural myocardial infarction. Next to inflammation mediating cells like monocytes, platelets play an essential role at early and late stages of atherosclerotic disorders. This review summarizes the basic pathophysiological mechanism of platelet adhesion and secretion, the molecular steps involved in platelet mediated thrombus formation in the atherosclerotic microenvironment and the role of platelet accumulation in reperfused myocardium.