Platelets have long been recognized as key players in hemostasis and thrombosis; however, growing evidence suggests that they are also significantly involved in cancer, the second leading cause of mortality worldwide. Preclinical and clinical studies showed that tumorigenesis and metastasis can be promoted by platelets through a wide variety of crosstalk between platelets and cancer cells. For example, cancer changes platelet behavior by directly inducing tumor-platelet aggregates, triggering platelet granule and extracellular vesicle release, altering platelet phenotype and platelet RNA profiles, and enhancing thrombopoiesis. Reciprocally, platelets reinforce tumor growth with proliferation signals, antiapoptotic effect, and angiogenic factors. Platelets also activate tumor invasion and sustain metastasis via inducing an invasive epithelial-mesenchymal transition phenotype of tumor cells, promoting tumor survival in circulation, tumor arrest at the endothelium, and extravasation. Furthermore, platelets assist tumors in evading immune destruction. Hence, cancer cells and platelets maintain a complex, bidirectional communication. Recently, aspirin (acetylsalicylic acid) has been recognized as a promising cancer-preventive agent. It is recommended at daily low dose by the US Preventive Services Task Force for primary prevention of colorectal cancer. The exact mechanisms of action of aspirin in chemoprevention are not very clear, but evidence has emerged that suggests a platelet-mediated effect. In this article, we will introduce how cancer changes platelets to be more cancer-friendly and highlight advances in the modes of action for aspirin in cancer prevention. We also discuss the opportunities, challenges, and opposing viewpoints on applying aspirin and other antiplatelet agents for cancer prevention and treatment.

Platelets are small anucleate blood cells generated from megakaryocytes in the bone marrow and cleared in the reticuloendothelial system. At the site of vascular injury, platelet adhesion, activation and aggregation constitute the first wave of hemostasis. Blood coagulation, which is initiated by the intrinsic or extrinsic coagulation cascades, is the second wave of hemostasis. Activated platelets can also provide negatively-charged surfaces that harbor coagulation factors and markedly potentiate cell-based thrombin generation. Recently, deposition of plasma fibronectin, and likely other plasma proteins, onto the injured vessel wall has been identified as a new "protein wave of hemostasis" that may occur even earlier than the first wave of hemostasis, platelet accumulation. Although no experimental evidence currently exists, it is conceivable that platelets may also contribute to this protein wave of hemostasis by releasing their granule fibronectin and other proteins that may facilitate fibronectin self- and non-self-assembly on the vessel wall. Thus, platelets may contribute to all three waves of hemostasis and are central players in this critical physiological process to prevent bleeding. Low platelet counts in blood caused by enhanced platelet clearance and/or impaired platelet production are usually associated with hemorrhage. Auto- and allo-immune thrombocytopenias such as idiopathic thrombocytopenic purpura and fetal and neonatal alloimmune thrombocytopenia may cause life-threatening bleeding such as intracranial hemorrhage. When triggered under pathological conditions such as rupture of an atherosclerotic plaque, excessive platelet activation and aggregation may result in thrombosis and vessel occlusion. This may lead to myocardial infarction or ischemic stroke, the major causes of mortality and morbidity worldwide. Platelets are also involved in deep vein thrombosis and thromboembolism, another leading cause of mortality. Although fibrinogen has been documented for more than half a century as essential for platelet aggregation, recent studies demonstrated that fibrinogen-independent platelet aggregation occurs in both gene deficient animals and human patients under physiological and pathological conditions (non-anti-coagulated blood). This indicates that other unidentified platelet ligands may play important roles in thrombosis and might be novel antithrombotic targets. In addition to their critical roles in hemostasis and thrombosis, emerging evidence indicates that platelets are versatile cells involved in many other pathophysiological processes such as innate and adaptive immune responses, atherosclerosis, angiogenesis, lymphatic vessel development, liver regeneration and tumor metastasis. This review summarizes the current knowledge of platelet biology, highlights recent advances in the understanding of platelet production and clearance, molecular and cellular events of thrombosis and hemostasis, and introduces the emerging roles of platelets in the immune system, vascular biology and tumorigenesis. ...

Platelets are central mediators of thrombosis and hemostasis. At the site of vascular injury, platelet accumulation (i.e. adhesion and aggregation) constitutes the first wave of hemostasis. Blood coagulation, initiated by the coagulation cascades, is the second wave of thrombin generation and enhance phosphatidylserine exposure, can markedly potentiate cell-based thrombin generation and enhance blood coagulation. Recently, deposition of plasma fibronectin and other proteins onto the injured vessel wall has been identified as a new “protein wave of hemostasis” that occurs prior to platelet accumulation (i.e. the classical first wave of hemostasis). These three waves of hemostasis, in the event of atherosclerotic plaque rupture, may turn pathogenic, and cause uncontrolled vessel occlusion and thrombotic disorders (e.g. heart attack and stroke). Current anti-platelet therapies have significantly reduced cardiovascular mortality, however, on-treatment thrombotic events, thrombocytopenia, and bleeding complications are still major concerns that continue to motivate innovation and drive therapeutic advances. Emerging evidence has brought platelet adhesion molecules back into the spotlight as targets for the development of novel anti-thrombotic agents. These potential antiplatelet targets mainly include the platelet receptors glycoprotein (GP) Ib-IX-V complex, β3 integrins (αIIb subunit and PSI domain of β3 subunit) and GPVI. Numerous efforts have been made aiming to balance the efficacy of inhibiting thrombosis without compromising hemostasis. This mini-review will update the mechanisms of thrombosis and the current state of antiplatelet therapies, and will focus on platelet adhesion molecules and the novel anti-thrombotic therapies that target them.

Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation. Incubation with exenatide also inhibited thrombus formation under flow conditions in ex vivo perfusion chambers using human and mouse whole blood. In a mouse cremaster artery laser injury model, a single intravenous injection of exenatide inhibited thrombus formation in normoglycemic and hyperglycemic mice in vivo. Thrombus formation was greater in mice transplanted with bone marrow lacking a functional GLP-1R (Glp1r 2/2 ), compared with those receiving wild-type bone marrow. Although antithrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r 2/2 mice, they were undetectable in mice with a genetic deficiency of endothelial nitric oxide synthase. The inhibition of platelet function and the prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events.Type 2 diabetes (T2D) is associated with a number of risk factors that contribute to an increased risk of atherothrombotic events, including hypertension, dyslipidemia, obesity, and chronic inflammation, as well as endothelial and platelet dysfunction (1). Platelets are small, versatile, anucleate cells in the circulation that play critical roles in both early and late stages of atherothrombosis, contributing also to cell-based thrombin generation and blood coagulation (2). Subjects with T2D exhibit a prothrombotic state, including increased production of coagulation factors; decreased production of fibrinolytic factors; and a propensity to platelet activation, aggregation, and adhesion (1,3,4). Compounding the latter, subjects with T2D show reduced sensitivity to antiplatelet drugs, such as aspirin and clopidogrel (5,6), and manifest a higher incidence of cardiovascular events (1,6,7). Although the currently available antidiabetic agents have been effective at lowering blood glucose levels and preventing microvascular disease, until the recent EMPA-REG study (8), it had been exceedingly difficult to demonstrate the beneficial effects of normalizing blood glucose

Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases.

Scope Platelet integrin αIIbβ3 is the key mediator of atherothrombosis. Supplementation of coenzyme Q10 (CoQ10), a fat‐soluble molecule that exists in various foods, exerts protective cardiovascular effects. This study aims to investigate whether and how CoQ10 acts on αIIbβ3 signaling and thrombosis, the major cause of cardiovascular diseases. Methods and results Using a series of platelet functional assays in vitro, it is demonstrated that CoQ10 reduces human platelet aggregation, granule secretion, platelet spreading, and clot retraction. It is further demonstrated that CoQ10 inhibits platelet integrin αIIbβ3 outside‐in signaling. These inhibitory effects are mainly mediated by upregulating cAMP/PKA pathway, where CoQ10 stimulates the A2A adenosine receptor and decreases phosphodiesterase 3A phosphorylation. Moreover, CoQ10 attenuates murine thrombus growth and vessel occlusion in a ferric chloride (FeCl3)‐induced thrombosis model in vivo. Importantly, the randomized, double‐blind, placebo‐controlled clinical trial in dyslipidemic patients demonstrates that 24 weeks of CoQ10 supplementation increases platelet CoQ10 concentrations, enhances the cAMP/PKA pathway, and attenuates αIIbβ3 outside‐in signaling, leading to decreased platelet aggregation and granule release. Conclusion Through upregulating the platelet cAMP/PKA pathway, and attenuating αIIbβ3 signaling and thrombus growth, CoQ10 supplementation may play an important protective role in patients with risks of cardiovascular diseases.

The aim of this prospective study was to propose a new rating system using a risk model including conventional ultrasound (US) and acoustic radiation force impulse (ARFI) elastography for predicting central lymph node metastasis (LNM) in patients with papillary thyroid microcarcinoma (PTMC).A total of 252 patients with PTMCs were enrolled, who were preoperatively evaluated by US and ARFI elastography including virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ). Risk factors of independent variables for central LNM were analyzed by univariate and multivariate analyses. A multivariate analysis was performed to create a predicting model and rating system.Of the 252 patients, 72 (28.6%) had central LNMs. Multivariate analysis revealed that rare internal flow (odds ratio [OR]: 4.454), multiple suspicious foci on US (OR: 5.136), capsule involvement (OR: 20.632), and VTI area ratio (VAR) > 1 (OR: 5.621) were independent risk factors for central LNM. The final predicting model was obtained and the risk score (RS) was defined as 1.5 × (if rare internal flow) + 1.6 × (if multiple suspicious foci on US) + 1.7 × (if VAR > 1) + 3.0 × (if capsule involvement). The rating system was divided into 5 stages. Stage I, <1.5; Stage II, 1.5 to 3.0; Stage III, 3.1 to 4.7; Stage IV, 4.8 to 6.3; and Stage V, 6.4 to 7.8. The risk rates of central LNM were 3.4% (2/59) in Stage I, 13.3% (13/98) in Stage II, 54.2% (39/72) in Stage III, 72.2% (13/18) in Stage IV, and 100% (5/5) in Stage V (P < 0.001).The results indicated that rare internal flow, multiple suspicious foci, capsule involvement on US, and VAR > 1 on ARFI elastography are the risk factors for predicting central LNM. The risk model developed in the study clearly predicts the risk of central LNM in patients with PTMC and thus has a potential to avoid unnecessary central compartment node dissection.

Malignant tumors are the major disease that cause serious damage to human health, and have been listed as the premier diseases which seriously threatened human health by World Health Organization (WHO). In recent years the development of antitumor drugs has been gradually transformed from cytotoxic drugs to improving the selectivity of drugs, overcoming multidrug resistance, development of new targeted drugs and low toxicity with high specificity drugs. Amygdalin is a natural product that owns antitumor activity, less side effects, widely sourced and relatively low priced. All these features make the amygdalin a promising antitumor drugs, if combined with conditional chemotherapy drugs, which can produce synergistic effect. In this paper, we summarized the pharmacological activity, toxicity and antitumor activity of amygdalin, mainly focused on the advanced research of amygdalin on its antitumor effects in recent years, providing new insights for the development of new anticancer drugs, new targets searching and natural antitumor mechanism investigations.