Current Vascular Pharmacology - Volume 10, Issue 5, 2012

Platelets are involved in vascular homeostasis and inflammation through interaction with circulating blood cells and vascular wall. MiRNAs are small, conserved and non-coding RNA molecules, which interact directly with specific mRNAs regions regulating gene expression. The purpose of this review is to gather all known platelet miRNAs and summarize their role in platelet biogenesis and function. Increasing evidence supports the role of miR-34a and miR-150 in megakaryocytopoiesis and platelet production. Although 284 miRNAs are described to be present in platelets, their role is mostly unknown. The most abundant miRNA in platelets is miR-223 followed by miR-126. The miR-96, miR-200b, miR- 495, miR-107 and miR-223 are critically involved in platelet reactivity, aggregation, secretion and adhesion. The presence of miRNAs known to regulate angiogenesis in platelets is also discussed. Furthermore, platelet-derived microvesicles and microparticles contain several miRNAs, which may facilitate the communication between platelets with other vascular cells, a mechanism that may play an important role in vascular homeostasis and inflammation. Further studies are needed to elucidate the exact roles of platelet miRNAs in platelet function and vascular biology.

Diabetes mellitus is associated with the accelerated development of vascular disease and there is evidence that platelets actively contribute to this process. Certainly, platelets are able to modulate the function of endothelial and vascular smooth muscle cells via the direct release of growth factors and pro-inflammatory chemokines but also via the production of microparticles which function as a transcellular delivery system for micro RNAs. This article reviews the intracellular signaling mechanisms underlying the increased activation of diabetic platelets and the involvement of platelets in atherothrombosis development.

Inflammation of the vascular wall is considered as the principal underlying mechanism in the development of atherosclerosis. Besides their specific functions in haemostasis via thrombus formation after an endothelial injury, a growing body of evidence indicates that platelets play an important role in the inflammatory reactions occurring in the vascular wall as well as in the subsequent tissue repair mechanisms. Platelets interact with activated endothelium as well as with circulating leukocytes and progenitor cells. These interactions, involve direct cell-to-cell interactions as well as autocrine and paracrine pathways, which lead to activation of platelets and their respective cellular counterpart. An increasing body of evidence suggests that antiplatelet therapy may reduce vascular inflammation primarily by inhibiting platelet activation. The aim of the present review is to highlight the molecular basis of platelet-mediated inflammatory response, focusing on the mechanisms underlying the platelet-endothelial cell interaction. The anti-inflammatory effects of current antiplatelet therapies will be also discussed.

Leukocyte rolling, adhesion, transmigration and activation are features of vascular inflammation leading to atherosclerosis. In particular the interaction between platelets and leukocytes is a key process for adhesion of inflammatory cells to the vascular wall. The various mechanisms of the specific platelet-leukocyte interaction may provide a powerful target to prevent initiation and/or progression of atherosclerotic lesions.

Platelet adhesion on vascular wall is the first step following vascular injury. Differential platelet secretion supports angiogenesis and vascular homeostasis. Progenitor cells are pluripotent cells responsible for tissue regeneration and wound healing. Upon ischemia bone marrow-derived progenitor cells are mobilized into peripheral circulation and domiciliate into peripheral organ vasculature and either give birth to a series of cardiovascular cells, including endothelial cells, macrophages, smooth muscle cells, or support in a paracrinic way the angiogenic capacity of local tissue cells. Mobilization, chemotaxis, adhesion, differentiation and interaction with vascular cells are essential steps of progenitor cellmediated tissue repair. This review summarizes the recent advances in our understanding of platelet function with focus on interaction with progenitor cells and its role in cardiovascular homeostasis. Moreover, the role of platelet microparticles in progenitor cell function is separately addressed. Understanding the mechanisms of platelet interaction with progenitor cells provides us with new insights in the mechanisms of vascular homeostasis and possible new therapeutical targets supporting vascular repair.

Over the past decade, platelets have been demonstrated to have various functions beyond their role in hemostasis. Platelets possess a rich repertoire of chemokines that are stored in their alpha granules and can be released upon activation. The pro-atherogenic effects of activated platelets are most likely mediated by release of these pro-inflammatory mediators that promote recruitment, activation or differentiation of other cell types including endothelial cells and leukocytes. These effects have been excellently reviewed in the past by various authors. The current review will therefore focus on novel findings. A specific focus will be put on CXCL4, on which a lot of new data have been published since 2008. Thus, the effects of CXCL4 on macrophage differentiation have been studied in detail revealing that CXCL4 induces a specific macrophage phenotype. Furthermore, novel data on CXCL4L1, a protein similar to CXCL4 that is probably transcribed from a duplication of the PF4 gene coding for CXCL4, will be discussed. A very interesting study has recently demonstrated that the inhibition of heterophilic chemokine interactions using a specifically designed small molecule can inhibit atherogenesis in Apoe-/- mice, thereby demonstrating the clinical potential of tackling platelet chemokines as therapeutic targets in atherosclerosis. Finally, novel data on CXCL1 and CCL5 will be discussed. Overall, while our understanding of the role of platelet chemokines in atherogenesis has significantly improved over the past years, it seems that there may still be many buried treasures in this field that could improve disease prevention or lead to novel clinical therapies.

Platelets hold an important function as first line of response to seal wounds after vascular and tissue injury. However, they are much more than just a component of the haemostatic system. They are involved in tissue regeneration and play a role in different pathologic conditions such as atherosclerosis or tumour progression. Angiogenesis being involved in these processes, as well, may represent one of the (patho-) physiological mechanisms, which are modulated by platelets thereby affecting disease. In other diseases involving inflammation, the role of platelets for endothelial cells, which are the most important cell type in angiogenesis, is well established. Recent effort has now highlighted a potential role of platelets and platelet derived mediators for angiogenesis. This article reviews our current understanding of the role of platelets for angiogenesis and how this knowledge could affect future directions in research and therapy.

Platelets are known to play a fundamental role in acute coronary syndromes. After atherosclerotic plaque rupture, platelets can form pathogenic, occlusive thrombi leading to acute ischemic events. Today there are promising results from recently developed antiplatelet agents. However, morbidity and mortality from acute coronary syndromes remain significant despite the administration of combination therapies (aspirin, thienopyridines). Sharing similar mechanisms, platelets may also form a thin monolayer in areas of damaged endothelium contributing to primary hemostasis. For this reason, administration of antiplatelet drugs is often associated with increased bleeding risk. As a result, currently available antiplatelet therapy cannot be characterized as optimal. The precise mechanisms of platelet activation in acute coronary syndromes are still under investigation. The study of basic mechanisms of platelet adhesion, activation and aggregation after atherosclerotic plaque rupture may help to define new targets for their inhibition. In the future, newer antiplatelet agents may offer more comprehensive platelet inhibition without interfering with primary hemostasis, thus offering greater protection with lower hemorrhagic risk.

Platelets and their activation have a pivotal role in the development of atherosclerotic diseases such as acute myocardial infarction (AMI), stroke and peripheral arterial occlusion. Biomarkers of platelet activation are making inroads into clinical studies and may serve as promising agents upstream to established downstream markers of myocardial necrosis such as troponin and creatin kinase. Targeting the degree of platelet activation assessed by the key collagen receptor of platelet activation, glycoprotein VI (GPVI), may have diagnostic and prognostic value for the assessement of high-risk groups of patients with symptomatic coronary artery disease and ischemic stroke and may be worthwhile to help to facilitate clinical decision-making and to rapidly initiate adequate therapy. The concert of platelet count, platelet activation, platelet aggregation and subsequent inflammation has had a significant impact on the clinical outcome in patients with atherosclerotic diseases. For a therapeutical approach to ameliorate prognosis, the use of antiplatelet treatment in particular in AMI patients with low response to clopidogrel has partly been overcome by novel second antiplatelet drugs on top of aspirin such as prasugrel and ticagrelor. Antiplatelet therapy may be adapted according to a GPVI-based platelet activity monitoring along with aggregometry of residual platelet aggregation. Other approaches using protease-activated receptor- 1 antagonists vorapaxar or atopaxar, which inhibit the platelet thrombin receptor, soluble GPVI called Revacept©, which blocks the collagen binding sites at the vascular lesion and anopheline saliva protein derived from the malaria vector mosquito, a platelet adhesion inhibitor independent of a GPVI mechanism, still wait for their breakthrough.

Stent thrombosis (ST) is a rare but very serious event complicating percutaneous coronary intervention (PCI) procedures. Both procedure- and patient-related factors, including inadequate platelet inhibition are well known predictors of ST. According to the present guidelines, a dual antiplatelet treatment regimen consisting of aspirin and a P2Y12 receptor inhibitor such as clopidogrel, prasugrel or ticagrelor is routinely administered to ACS patients and to patients undergoing PCI in order to prevent thrombotic vessel occlusions. In recent years, evidence has grown that patients showing high on-treatment platelet reactivity (HPR) under clopidogrel intake exhibit a higher risk for the occurrence of ischemic events including ST. For assessing HPR, different platelet function assays are currently available and have already found their way into routine clinical practice in several centers. Along with this development, more potent P2Y12 receptor inhibitors like prasugrel and ticagrelor are substitutes for clopidogrel in specific circumstances such as in ACS patients or in patients who do not adequately respond to standard clopidogrel treatment. Utilizing platelet function monitoring, patients showing HPR can be identified and an optimized antiplatelet treatment regime can be tailored for these patients. This review paper aims to summarize the important facts in relation to ST and antiplatelet therapy with a particular focus on P2Y12 receptor inhibition and its ex vivo assessment in patients undergoing coronary stent placement.

Acute coronary syndromes (ACS) are triggered by enhanced platelet activation and aggregation. Hence, a cornerstone of successful secondary prevention in ACS is an effective platelet inhibition. Additionally, coronary interventions (PCI) lead to even increased artherothrombotic risks, another challenge in preventing recurrent events including stent thrombosis. Promising platelet targets were characterized and novel molecules were developed that are currently under investigation. Intensified antiplatelet therapy includes the risk of major bleeding which itself increases the mortality rate. Previous strategies of antiplatelet therapy were based on an “one-size fits all” concept. However, there has been evidence that variability of drug response exists and represents a clinically relevant issue. This observation is in line with results of randomized clinical trials that standard-of-care antiplatelet therapy is not sufficient to reduce cardiovascular (CV) risk in certain subgroups of ACS patients. In the last years, novel antiplatelet substances have entered the clinical arena and others are currently under investigation in phase II and III clinical trials. These include 3rd generation thienopyridine (prasugrel, elinogrel), ATP analogs (Ticagrelor, cangrelor), and non-ADP-receptor blocking antiplatelet substances like thrombin receptor antagonists. These agents have shown promising results in pilot studies and recent randomized trials. As the prevention of atherothrombotic risk is at the expense of bleeding risk, it will be a future task to clearly define patients’ groups and subsets of ACS for the best net clinical benefit. This article focuses on the role of novel antiplatelet substances to reduce CV risk in ACS, discuss clinical implications and their potential future role.

Coronary artery disease remains a major hazard within the western world despite early revascularisation and advanced medical therapy strategies. One of its major substrates is platelet activation and thrombus formation, triggering acute events such as myocardial infarction and ischemic strokes. There are a variety of non-invasive imaging strategies being translated from bench to bedside into clinical practice that tackle specific aspects of the pathophysiology of thrombus formation. Some of those techniques are able to visualize native contrast differences between thrombus and surrounding tissue, others focus on the use of specific contrast agents targeting thrombotic components such as fibrin or activated platelets. Some of those techniques are still in the pre-clinical stage; others have already entered the clinical arena. The current review article will introduce different techniques and their stage of development on their way from bench to bedside with a specific focus on cardiac magnetic resonance imaging, that has evolved over the last years providing high quality information on anatomy, perfusion and myocardial tissue characteristics such as scarring in clinical practice. Finally, we will give an outlook on how this exciting field might evolve in the future.

Vascular risk factors and atherosclerosis are critically involved in dementia development of both vascular and Alzheimer’s type. However, the exact mechanisms linking atherosclerosis and the development of Alzheimer’s disease (AD) are still unknown. As platelet activation and adhesion on vascular wall is the first step of vascular inflammation and atherosclerosis, it appears tempting to hypothesize that platelets could be the link between vascular risk factors/ atherosclerosis and AD. In recent years, much work has been accomplished to elucidate the role of platelets in AD. The present review will summarize and highlight the latest findings of this research area and provide novel insight and understanding in the association between platelet activation and AD.

Sepsis results in the concurrent activation of inflammatory and procoagulant pathways. Bacterial products and proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C (APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism. Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 – PAR1 dependent (macrophages) mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.

Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis with increased mortality largely attributable to cardiovascular disease. There is extensive evidence that patients with RA experience accelerated atherosclerosis, which is considered as the main responsible of this increased cardiovascular burden. Nowadays atherosclerosis is regarded as an inflammatory condition: hence, the cumulative inflammation of RA, with the abundant synthesis of proinflammatory cytokines, contributes directly to the early formation of the atheromatic plaque. It is therefore reasonable to postulate that, by alleviating inflammation, drugs commonly used in RA treatment may ameliorate the cardiovascular profile of these patients. Here we provide an extensive review of the literature, focusing on the effects of the available anti-rheumatic agents on cardiovascular mortality, and morbidity among RA sufferers.

Inflammation and coagulation systems are simultaneously activated in autoimmune and immune-mediated skin disorders, and the cross-talk that amplifies and maintains their activation seems to have both local and systemic implications. This interplay occurs in bullous pemphigoid (BP), the prototype autoimmune blistering disease in which eosinophil recruitment and thrombin generation locally contribute to the formation of bullae and inflammatory tissue damage. Moreover, the systemic activation of coagulation may explain the increased thrombotic risk observed in BP patients. Atopic dermatitis (AD), a chronically relapsing immune-mediated inflammatory skin disease, also involves the local and systemic activation of coagulation, which means that a prothrombotic state could theoretically develop, although the incidence of thrombosis is not increased in AD patients probably because of their young age. In psoriasis, a erythematoussquamous inflammatory immune-mediated skin disorder, the activation of coagulation seems to be mainly systemic and related to systemic inflammation, thus potentially contributing to the disease-related increase in cardiovascular risk in this disease. The activation of coagulation has also been suggested an additional pathomechanism in dermatitis herpetiformis (DH), a chronic-relapsing autoimmune skin disease associated with gluten sensitivity and celiac disease, but its precise role has not yet been defined. Taken together, these data provide the rationale for controlled clinical trials aimed at evaluating the usefulness of anticoagulant treatment in autoimmune skin disorders to counteract the local and systemic effects of coagulation activation.

Urticaria is a skin disease characterised by short-lived surface swellings of the dermis (wheals) frequently accompanied by itching. It is classified as acute or chronic depending on whether the wheal recurrence occurs for less or more than six weeks. Acute urticaria is often due to a hypersensitivity reaction, whereas about 50% of the cases of chronic urticaria are regarded as autoimmune. Urticaria may occur alone or in association with a deeper swelling (angioedema) involving the subcutaneous and/or submucosal tissues, and last from hours to a few days. Angioedema can also develop alone, and may be idiopathic or be caused by allergies, inherited or acquired deficiencies of C1-inhibitor protein, or adverse drug reactions. An interplay between inflammation and coagulation has been proposed as a pathomechanism in urticaria and urticaria-associated angioedema (in which histamine and thrombin are involved), as well as in angioedema due to C1-inhibitor deficiency, which involves various biological systems. An increase in the plasma markers of thrombin generation, fibrinolysis and inflammation has been documented during exacerbations of urticaria and angioedema, with the marker levels decreasing to normal during remission. However, the hypercoagulable state in chronic urticaria and angioedema has not been reported to be associated with any increased risk of thrombosis, although there have been a number of reports of cardiovascular events occurring during episodes of acute urticaria. These observations have provided the rationale for the clinical evaluation of anticoagulant and antifibrinolytic drugs, the efficacy of which has sometimes been demonstrated.

Inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis (UC) are idiopathic, intestinal and systemic inflammatory disorders which are immunologically mediated with the activation of plasma proteolytic cascades. The activation of coagulation in IBD is related to the activity and colonic extension of the disease, but may still be persistent in a quiescent stage. Factor XIII seems to be as much a coagulation factor as a connective tissue factor which may contribute to intestinal healing. Fibrinolytic capacity is reduced in systemic circulation of IBD patients. Platelets activation is a feature of IBD which contributes to a pathogenic inflammatory sequel. There is evidence that coagulation activation may in turn mediate and amplify inflammatory cascades in IBD, especially via activating PARs related pathways. The etiology of thromboembolism in IBD seems to be multifactorial but is largely attributable to the coagulation activation and platelet aggregation during systemic inflammation. Thromboembolic (TE) complications in both Crohn’s disease and UC appear to have at least 3-4 fold increased risk of developing compared to control patients. Currently, no single TE laboratory marker has a predictive value, but a recently developed endogenous thrombin potential test may have a potentially predicative value in IBD. At present, no interaction between IBD and inherited factors of thrombophilia has been found. An efficacy of heparin treatment in UC is still controversial, although heparin is safe in UC flare. Prophylactic anticoagulation against TE is currently not fully defined, however, high - risk patients should be considered for using a moderate dose of heparin.