The Aging Population and Research into Treatments for Abdominal Aortic Aneurysms.

Abdominal aortic aneurysms (AAAs) usually expand asymptomatically until the occurrence of a life-threatening event such as aortic rupture, which is closely associated with high mortality. AAA and aortic dissection are ranked among the top 10 causes of death in Japan. The major risk factors for AAA are age over 65 years, male gender, family history, and smoking. Thus, for prevention, smoking cessation is the most important lifestyle-intervention. For treatment, since AAA generally affects elderly people, less invasive treatment is preferable. However, the only established treatment for AAA is open repair and endovascular repair. This review describes potential medical treatments to slow aneurysm growth or prevent AAA rupture.

From head to toe: Sex and gender differences in the treatment of ischemic cerebral disease.

Stroke is a major cause of mortality and morbidity, particularly in the older ages. Women have a longer life expectancy and are more likely to experience stroke than men. Interestingly, the increased risk of ischemic stroke in women seems to be independent from age or classical cardiovascular risk factors. Notwithstanding the fact that stroke outcomes and survival are usually poorer in women, current evidence suggests that thrombolysis, antiplatelet and anticoagulant therapies are more beneficial in women than in men. A possible explanation of this paradox might be that females are often undertreated and they have fewer chances to be submitted to an effective and timely treatment for stroke than the male counterpart. The first step in the attempt to solve this obvious discrimination is surely to emphasize any reasons for differences in the therapeutic approach in relation to gender and then to denounce the lack of a sustainable motivation for them. In this article, we aimed to review the existing literature about gender-related differences on efficacy, administration and side effects of the most common drugs used for the treatment of ischemic stroke. The most striking result was the evidence that the therapeutic approach for stroke is often different according to patients' gender with a clear detrimental prognostic effect for women. A major effort is necessary to overcome this problem in order to ensure equal right to treatment without any sexual discrimination.

Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma.

Previous studies in mouse models of self-limited viral hepatitis showed that platelets contribute to acute liver damage by promoting the intrahepatic accumulation of virus-specific CD8 T cells and, secondarily, virus-non-specific inflammatory cells. Built on these observations, a recent preclinical study took advantage of a previously established hepatitis B virus (HBV) transgenic mouse model of immune-mediated chronic hepatitis that progresses to hepatocellular carcinoma (HCC), to demonstrate that clinically achievable doses of the anti-platelet drugs aspirin and clopidogrel - administered continuously after the onset of liver disease - can prevent hepatocarcinogenesis and greatly improve overall survival. These outcomes were preceded by and associated with reduced hepatic accumulation of virus-specific CD8 T cells and virus-non-specific inflammatory cells, reduced hepatocellular injury and hepatocellular proliferation, and reduced severity of liver fibrosis. The observation that anti-platelet therapy inhibits HCC development identifies platelets as key players in the pathogenesis of HBV-associated liver cancer and supports the notion that a sustained immune-mediated necroinflammatory liver disease is sufficient to trigger HCC. The results abovementioned and their clinical implications are discussed in this report.

[Inhibition of platelet aggregation (Update 2023)]. / Thrombozytenaggregationshemmer (Update 2023).

Acute thrombotic complications as a key feature of accelerated atherothrombotic disease typically precipitate cardiovascular events and therefore strongly contribute to cardiovascular morbidity and mortality in patients with diabetes. Inhibition of platelet aggregation can reduce the risk for acute atherothrombosis. The present article represents the recommendations of the Austrian Diabetes Association for the use of antiplatelet drugs in patients with diabetes according to current scientific evidence.

The Detrimental Role of Intraluminal Thrombus Outweighs Protective Advantage in Abdominal Aortic Aneurysm Pathogenesis: The Implications for the Anti-Platelet Therapy.

Abdominal aortic aneurysm (AAA) is a common cardiovascular disease resulting in morbidity and mortality in older adults due to rupture. Currently, AAA treatment relies entirely on invasive surgical treatments, including open repair and endovascular, which carry risks for small aneurysms (diameter < 55 mm). There is an increasing need for the development of pharmacological intervention for early AAA. Over the last decade, it has been increasingly recognized that intraluminal thrombus (ILT) is involved in the growth, remodeling, and rupture of AAA. ILT has been described as having both biomechanically protective and biochemically destructive properties. Platelets are the second most abundant cells in blood circulation and play an integral role in the formation, expansion, and proteolytic activity of ILT. However, the role of platelets in the ILT-potentiated AAA progression/rupture remains unclear. Researchers are seeking pharmaceutical treatment strategies (e.g., anti-thrombotic/anti-platelet therapies) to prevent ILT formation or expansion in early AAA. In this review, we mainly focus on the following: (a) the formation/deposition of ILT in the progression of AAA; (b) the dual role of ILT in the progression of AAA (protective or detrimental); (c) the function of platelet activity in ILT formation; (d) the application of anti-platelet drugs in AAA. Herein, we present challenges and future work, which may motivate researchers to better explain the potential role of ILT in the pathogenesis of AAA and develop anti-platelet drugs for early AAA.

Mechanism and Potential Target of Blood-Activating Chinese Botanical Drugs Combined With Anti-Platelet Drugs: Prevention and Treatment of Atherosclerotic Cardiovascular Diseases.

Atherosclerotic cardiovascular diseases (ASCVDs) are the most important diseases that endanger people's health, leading to high morbidity and mortality worldwide. In addition, various thrombotic events secondary to cardiovascular and cerebrovascular diseases need must be considered seriously. Therefore, the development of novel anti-platelet drugs with high efficiency, and fewer adverse effects has become a research focus for preventing of cardiovascular diseases (CVDs). Blood-activation and stasis-removal from circulation have been widely considered as principles for treating syndromes related to CVDs. Blood-activating Chinese (BAC botanical drugs, as members of traditional Chinese medicine (TCM), have shown to improve hemodynamics and hemorheology, and inhibit thrombosis and atherosclerosis. Modern medical research has identified that a combination of BAC botanical drugs and anti-platelet drugs, such as aspirin or clopidogrel, not only enhances the anti-platelet effects, but also reduces the risk of bleeding and protects the vascular endothelium. The anti-platelet mechanism of Blood-activating Chinese (BAC) botanical drugs and their compounds is not clear; therefore, their potential targets need to be explored. With the continuous development of bioinformatics and "omics" technology, some unconventional applications of BAC botanical drugs have been discovered. In this review, we will focus on the related targets and signaling pathways of anti-atherosclerotic treatments involving a combination of BAC botanical drugs and anti-platelet drugs reported in recent years.

Platelets: the point of interconnection among cancer, inflammation and cardiovascular diseases.

INTRODUCTION: The association between thrombosis, cancer and inflammation is well-established. Platelets play a major role in atherosclerosis, inflammation and immune response. Furthermore, growing evidence suggests that they are also significantly involved in tumor development and progression so that anti-platelet agents may prevent cancer and improve outcomes in oncological patients. In this review, we aimed at analyzing the relationship between platelets, cardiovascular diseases and cancer. A comprehensive study in the main educational platforms was performed and high-quality original articles and reviews were included. AREAS COVERED: This review will focus on the role of platelets in cardiovascular disease and in cancer genesis and progression, analyzing their function as immune cells that link inflammation to thrombosis. Finally, it will examine the recent controversies on the use of anti-platelet agents as cancer medications, in particular the already known anti-tumor properties of aspirin, as well as the new perspectives regarding P2Y12 inhibitors. EXPERT OPINION: Platelet-cancer crosstalk generates a vicious feed-back loop involving tumor cells and secreting molecules that activate platelets, which in turn promote cancer-associated inflammation, proliferation, spreading and immune system evasion. Therefore, platelets inhibition may represent an innovative therapeutical strategy offered to cancer patients, in the perspective of personalized medicine.

Platelet Activation and the Immune Response to Tuberculosis.

In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which leads to both acute morbidity and mortality. Tissue destruction in TB is driven by host innate immunity and mediated via enzymes, chiefly matrix metalloproteinases (MMPs) which are secreted by leukocytes and stromal cells and degrade the extracellular matrix. Here we review the growing evidence implicating platelets in TB immunopathology. TB patients typically have high platelet counts, which correlate with disease severity, and a hypercoagulable profile. Platelets are present in human TB granulomas and platelet-associated gene transcripts are increased in TB patients versus healthy controls. Platelets most likely drive TB immunopathology through their effect on other immune cells, particularly monocytes, to lead to upregulation of activation markers, increased MMP secretion, and enhanced phagocytosis. Finally, we consider current evidence supporting use of targeted anti-platelet agents in the treatment of TB due to growing interest in developing host-directed therapies to limit tissue damage and improve treatment outcomes. In summary, platelets are implicated in TB disease and contribute to MMP-mediated tissue damage via their cellular interactions with other leukocytes, and are potential targets for novel host-directed therapies.

Why are antithrombotic drugs not prescribed to octogenarian patients with atrial fibrillation at risk of stroke?

OBJECTIVE: In non-valvular atrial fibrillation (NVAF) patients at risk of stroke, anticoagulant drugs are less likely to be received by older patients than younger patients. In this study, an attempt is made to discover whether the reasons reported by physicians for denying anticoagulant drugs prescription differ between older and younger atrial fibrillation patients. MATERIALS AND METHODS: A retrospective, cross-sectional, multicentre study was conducted from October 2014 to July 2015. The study comprised patients aged ≥18 years diagnosed with NVAF, with a moderate to high stroke risk (CHADS2 score ≥2). Patients were stratified according to age (<80 and ≥80 years). RESULTS: A total of 1309 NVAF patients were evaluated, of whom 40.1% were ≥80 years old. Older patients were predominantly women with higher mean time since diagnosis of AF, with a higher rate of permanent NVAF, and with higher thromboembolic risk. In patients for whom physicians decided not to prescribe any anticoagulant agents, the following reasons were significantly more frequent in patients aged ≥80 years compared to younger patients: cognitive impairment, perceived high bleeding risk, falls, difficult access to monitoring, non-neoplastic terminal illness, and perceived low thromboembolic risk. Uncontrolled hypertension was a significantly more frequent reason for non-prescription of anticoagulant agents in patients aged <80 year. CONCLUSIONS: Octogenarian patients with NVAF and a moderate to high risk of stroke had a different as regards reasons for not being prescribed anticoagulant agents, which should be taken into account in order to improve.

Platelets in cardiac ischaemia/reperfusion injury: a promising therapeutic target.

Acute myocardial infarction (AMI) is the single leading cause of mortality and morbidity worldwide. A key component of AMI therapy is the timely reopening of occluded vessels to prevent further ischaemic damage to the myocardium. However, reperfusion of the ischaemic myocardium can itself trigger reperfusion injury causing up to 50% of the overall infarct size. In recent years, considerable research has been devoted to understanding the pathogenesis of ischaemia/reperfusion (I/R) injury and platelets have emerged as a major contributing factor. This review summarizes the role of platelets in the pathogenesis of I/R injury and highlights the potential of platelet-directed therapeutics to minimize cardiac I/R injury. Activated platelets infiltrate specifically into the ischaemic/reperfused myocardium and contribute to I/R injury by the formation of microthrombi, enhanced platelet-leucocyte aggregation, and the release of potent vasoconstrictor and pro-inflammatory molecules. This review demonstrates the benefits of platelet inhibition beyond their well-described anti-thrombotic effect and highlights the direct cardioprotective role of anti-platelet drugs. In particular, the inhibition of COX, the P2Y12 receptor and the GPIIb/IIIa receptor has demonstrated the potential to attenuate I/R injury. Moreover, targeting of drug candidates or regenerative cells to the activated platelets accumulated within the ischaemic/reperfused myocardium shows remarkable potential to protect the myocardium from I/R injury. Overall, activated platelets play a key role in the pathogenesis of I/R injury. Their direct inhibition as well as their use as epitopes for site-directed therapy is a unique and promising therapeutic approach for the prevention of I/R injury and ultimately the preservation of cardiac function.

Venous Thromboembolism in Patients With Thrombocytopenia: Risk Factors, Treatment, and Outcome.

BACKGROUND: Venous thromboembolism (VTE) is a frequent and potentially lethal condition. Venous thrombi are mainly constituted of fibrin and red blood cells, but platelets also play an important role in VTE formation. Information about VTE in patients with thrombocytopenia is, however, missing. OBJECTIVES: To identify VTE risk factors and describe treatment and outcome (bleeding episodes and mortality) in patients with thrombocytopenia. PATIENTS/METHODS: Patients with thrombocytopenia (platelet count <100 × 109/L) admitted to Odense University Hospital, Denmark, between April 2000 and April 2012 were included. Fifty cases had experienced VTE. Controls without VTE were matched 3:1 with cases on sex and hospital department. Medical records were examined, and data were analyzed using conditional logistic regression. RESULTS: In multivariate analysis, platelet count <50 × 109/L (odds ratio [OR] 0.22, P < .05) and chronic liver disease (OR 0.05, 95% confidence interval [CI] 0.01-0.58) reduced the risk of VTE. Surgery (OR 6.44, 95% CI 1.37-30.20) and previous thromboembolism (OR 6.16, 95% CI 1.21-31.41) were associated with an increased VTE risk. Ninety-two percent of cases were treated with anticoagulants. There was no difference in bleeding incidence between cases and controls. CONCLUSIONS: Several known VTE risk factors also seems to apply in patients with thrombocytopenia. Also, patients with thrombocytopenia may be VTE risk stratified based on platelet count and comorbidities. Finally, patients having thrombocytopenia with VTE seem to be safely treated with anticoagulants without increased occurrence of bleeding.

Pannexin1 Single Nucleotide Polymorphism and Platelet Reactivity in a Cohort of Cardiovascular Patients.

Pannexin1 (Panx1), a membrane channel-forming protein permitting the passage of small-sized molecules, such as ATP, is expressed in human platelets. Recently, we showed that inhibiting Panx1 affects collagen-induced platelet aggregation but not aggregation triggered by other agonists. We also found that a single nucleotide polymorphism (SNP; rs1138800) in the Panx1 gene encoded for a gain-of-function channel (Panx1-400C) and was associated with enhanced collagen-induced platelet reactivity. Here, we assessed the association of this SNP with platelet reactivity in a cohort of 758 stable cardiovascular patients from the ADRIE study treated with aspirin and/or clopidogrel. We found that presence of the Panx1-400C allele was not associated with platelet reactivity in stable cardiovascular patients, irrespective of the platelet aggregation agonist used (collagen, ADP or arachidonic acid) or the anti-platelet drug regimen. Moreover, the Panx1-400A > C SNP did also not affect the re-occurrence of cardiac ischemic events in the same stable cardiovascular patient cohort.

Opportunities for improvement in anti-thrombotic therapy and other strategies for the management of acute coronary syndromes: Insights from EPICOR, an international study of current practice patterns.

AIMS: To describe international patterns and opportunities for improvement of pre- and in-hospital care of patients hospitalized for acute coronary syndromes (ACS), with special focus on anti-thrombotic therapy. METHODS AND RESULTS: EPICOR (long-tErm follow-uP of anti-thrombotic management patterns In acute CORonary syndrome patients), an international, cohort study, which enrolled 10,568 consecutive ACS survivors from 555 hospitals in 20 countries across Europe and Latin America (September 2010 to March 2011), prospectively registered detailed information on pre- and in-hospital management. Globally, 4738 (44.8%) were attended before hospitalization, 4241 (40.1%) had an ECG, 2119 (20%) received anti-platelet therapy and 101 STEMI patients (2%) fibrinolysis. In-hospital, 7944 patients (75.2%) received dual anti-platelet therapy, most often with clopidogrel (69.7%), and less with prasugrel (5.4%); 1705 (16.1%) had triple anti-platelet therapy, and 849 (8%) single anti-platelet therapy. STEMI patients more often received pre-hospital anti-thrombotics, and prasugrel, GP IIb/IIIa inhibitors and UFH in-hospital (all p < 0.001). More NSTE-ACS patients received clopidogrel, single anti-platelet therapy, and fondaparinux (all p < 0.001). As many as 33% of ACS patients were medically managed. A significant decreasing gradient was found between Northern, Southern and Eastern Europe and Latin America in use of more potent patterns of anti-platelet therapy, reperfusion therapy and invasive strategy. CONCLUSION: This large international study shows room for improvement in use of anti-thrombotic drugs and other strategies for optimal management of ACS, including pre-hospital ECG and anti-thrombotic therapy. Regional practice differences not based on evidence or conditioned by economic constraints should be reduced.

[Inhibition of platelet aggregation]. / Thrombozytenaggregationshemmer.

Acute thrombotic complications as a key feature of accelerated atherothrombotic disease typically precipitate cardiovascular events and therefore strongly contribute to cardiovascular morbidity and mortality in diabetic patients. Inhibition of platelet aggregation can reduce the risk for acute atherothrombosis. The present article represents the recommendations of the Austrian Diabetes Association for the use of antiplatelet drugs in diabetic patients according to current scientific evidence.

Effectiveness and safety of warfarin and anti-platelet drugs for the primary prevention of stroke in patients with non-valvular atrial fibrillation: a meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of warfarin and anti-platelet drugs as the primary approach to the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). METHODS: Three English databases (the Cochrane library, Embase, and Medline), and three Chinese databases (the Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, and Chinese Periodical Full-text Database of Science and Technology) were searched to select potentially eligible studies published before May, 2014. The studies were randomized controlled trials (RCTs) that investigated the effectiveness and safety of using warfarin and anti-platelet drugs in preventing stroke in NVAF patients; The statistical analysis was performed using the Review Manager 5.2 software provided by the Cochrane Collaboration. RESULTS: nine articles were finally included. Compared with antiplatelet drugs, warfarin treatment significantly reduced the risk of stroke (OR = 0.62, 95% CI 0.50-05.77), systemic embolism events (OR = 0.49, 95% CI 0.31-0.77), ischemic stroke events (OR = 0.46, 95% CI 0.36-0.59), stroke-related disability or death events (OR = 0.66, 95% CI 0.52-0.84). Warfarin did not increase the incidence of All-cause death events (OR = 0.92, 95% CI 0.78-1.08), intracranial hemorrhage events (OR = 1.28, 95% CI 0.85-1.93), major hemorrhage events (OR = 1.01, 95% CI 0.79-1.29). CONCLUSIONS: This meta-analysis found that compared with antiplatelet drugs, warfarin treatment significantly reduced the risk of stroke, systemic embolism events, ischemic stroke events, stroke-related disability or death events. And warfarin did not increase the incidence of All-cause death events, intracranial hemorrhage events, major hemorrhage events.

How do we manage serious gastrointestinal adverse events associated with anti-thrombotic therapy?

Antithrombotic therapy (ATTs) is increasingly used worldwide for preventing primary or recurrent thrombotic events. Moreover, newer oral anti-platelet drugs and anti-coagulants have been introduced for clinical use, accelerating the number of patients under ATT. Not infrequently, these drugs are used in combination. These drugs, however, are well-known for adverse events in which gastrointestinal bleeding (GIB) is most common. Bleeding during ATT can be fatal, but even when patients survive, their prognosis is rather poor. Therefore, it is imperative to minimize such events. So far, co-prescription of proton pump inhibitor (PPI) has been documented to be the most effective in reducing upper GI injury and bleeding, though deliberate use of PPIs is required to minimize drug interaction and associated adverse events with acid suppression. In addition, we should note that PPI is not effective in preventing mid- or lower-GI injury/bleeding for which only limited evidence on preventive measures is available.

Ambient hemolysis and activation of coagulation is different between HeartMate II and HeartWare left ventricular assist devices.

BACKGROUND: Thromboembolic and bleeding events in patients with a left ventricular assist device (LVAD) are still a major cause of complications. Therefore, the balance between anti-coagulant and pro-coagulant factors needs to be tightly controlled. The principle hypothesis of this study is that different pump designs may have an effect on hemolysis and activation of the coagulation system. Referring to this, the HeartMate II (HMII; Thoratec Corp, Pleasanton, CA) and the HeartWare HVAD (HeartWare International Inc, Framingham, MA) were investigated. METHODS: For 20 patients with LVAD support (n = 10 each), plasma coagulation, full blood count, and clinical chemistry parameters were measured. Platelet function was monitored using platelet aggregometry, platelet function analyzer-100 system ( Siemens, Marburg, Germany), vasodilator-stimulated phosphoprotein phosphorylation assay, immature platelet fraction, platelet-derived microparticles, and von Willebrand diagnostic. RESULTS: Acquired von Willebrand syndrome could be detected in all patients. Signs of hemolysis, as measured by lactate dehydrogenase levels (mean, 470 U/liter HMII, 250 U/liter HVAD; p < 0.001), were more pronounced in the HMII patients. In contrast, D-dimer analysis indicated a significantly higher activation of the coagulation system in HVAD patients (mean, 0.94 mg/liter HMII, 2.01 mg/liter HVAD; p < 0.01). The efficacy of anti-platelet therapy using clopidogrel was not sufficient in more than 50% of the patients. CONCLUSIONS: Our results support the finding that all patients with rotary blood pumps suffered from von Willebrand syndrome. In addition, a distinct footprint of effects on hemolysis and the coagulation system can be attributed to different devices. As a consequence, the individual status of the coagulation system needs to be controlled in long-term patients.

In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel.

INTRODUCTION: Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model. METHODS: The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values. RESULTS: PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline. CONCLUSIONS: Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings.

Anti-platelet agents in pediatric cardiac practice.

Pediatric patients with a variety of congenital and acquired cardiac conditions receive antithrombotic therapy. Many of the indications are empirical, and have either not been proven in controlled studies or are extrapolated from adult studies. This article reviews the current available literature regarding the use of anti-platelet drugs in the pediatric cardiac population.

Past, present, and future of anti-platelet therapy.

INTRODUCTION: Anti-platelet drugs are useful in preventing unwanted clots, but the complexities of platelet activation and clot formation are challenging. BACKGROUND: Platelets can be activated by a variety of agents, including natural biomolecules, foreign materials, and drugs. Calcium mediates a number of the intracellular processs Once activated, platelets release factors that act on other circulating cells and vascular endothelial cells to promote formation of a clot. The original anti-platelet drug, aspirin, inhibits cyclooxegenase, interfering with a crucial step in the biochemical cascade. Aspirin is cost-effective but limited in its application. Newer drugs, ticlopidine and clopidogrel, act on the activation pathway at different points, so they can supplement aspirin. NEW DIRECTIONS: Abciximab represents a new generation of antiplatelet drug, being an antibody that binds to platelet surface receptors, thus inhibiting growth of thrombus. Other potential sites for antibody intervention are extracellular matrix and endothelial surface components. As new drugs are developed it becomes more imperative to find assays of platelet function that are sensitive and cost-effective. CONCLUSION: Although much progress has been made in anagement of clotting significant opportunities and challenges remain, both in treatment and in measurement of treatment effectiveness.