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"Platelets"
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Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: open label, blinded endpoint, randomised controlled phase II trial
AbstractObjectiveTo test the hypothesis that ticagrelor plus aspirin is safe and superior to clopidogrel plus aspirin for reducing high platelet reactivity at 90 days and stroke recurrence in patients with minor stroke or transient ischaemic attack, particularly in carriers of the CYP2C19 loss-of-function allele and patients with large artery atherosclerosis.DesignOpen label, blinded endpoint, randomised controlled phase II trial.SettingProspective studies conducted at 26 centres in China, August 2015 to March 2017.Participants675 patients with acute minor stroke or transient ischaemic attack.InterventionTicagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 mg loading dose, 75 mg daily thereafter) on a background of aspirin (100 mg daily for the first 21 days) within 24 hours of symptom onset.Main outcome measuresPrimary outcome was the proportion of patients with high platelet reactivity at 90 days. High platelet reactivity was defined as P2Y12 reaction units of more than 208. Secondary outcomes included high platelet reactivity at 90 days (7 days either way) in patients carrying genetic variants that would affect clopidogrel metabolism, and any stroke (ischaemic or haemorrhagic) recurrence at 90 days (7 days either way), six months, and one year.ResultsAt 90 days, high platelet reactivity occurred in 35 (12.5%) of 280 patients in the ticagrelor/aspirin group and 86 (29.7%) of 290 patients in the clopidogrel/aspirin group (risk ratio 0.40; 95% confidence interval 0.28 to 0.56; P<0.001), and in 10.8% versus 35.4% (0.31; 0.18 to 0.49; P<0.001) of patients carrying CYP2C19 loss-of-function alleles. Stroke occurred in 21 (6.3%) of 336 patients in the ticagrelor/aspirin group and 30 (8.8%) of 339 patients in the clopidogrel/aspirin group (hazard ratio 0.70; 95% confidence interval 0.40 to 1.22; P=0.20). Patients with large artery atherosclerosis in the ticagrelor/aspirin group had a lower stroke recurrence at 90 days than those in the clopidogrel/aspirin group (6.0% v 13.1%; hazard ratio 0.45, 95% confidence interval 0.20 to 0.98; P=0.04). No difference was seen in the rates of major or minor haemorrhagic events between the ticagrelor/aspirin and clopidogrel/aspirin groups (4.8% v 3.5%; P=0.42).ConclusionPatients with minor stroke or transient ischaemic attack who are treated with ticagrelor plus aspirin have a lower proportion of high platelet reactivity than those who are treated with clopidogrel plus aspirin, particularly for those who are carriers of the CYP2C19 loss-of-function allele. The results of this study should be evaluated further in large scale, phase III trials and in different populations.Trial registrationClinicaltrials.gov NCT02506140.
Journal Article
Platelet Aggregometry Testing: Molecular Mechanisms, Techniques and Clinical Implications
Platelets play a fundamental role in normal hemostasis, while their inherited or acquired dysfunctions are involved in a variety of bleeding disorders or thrombotic events. Several laboratory methodologies or point-of-care testing methods are currently available for clinical and experimental settings. These methods describe different aspects of platelet function based on platelet aggregation, platelet adhesion, the viscoelastic properties during clot formation, the evaluation of thromboxane metabolism or certain flow cytometry techniques. Platelet aggregometry is applied in different clinical settings as monitoring response to antiplatelet therapies, the assessment of perioperative bleeding risk, the diagnosis of inherited bleeding disorders or in transfusion medicine. The rationale for platelet function-driven antiplatelet therapy was based on the result of several studies on patients undergoing percutaneous coronary intervention (PCI), where an association between high platelet reactivity despite P2Y12 inhibition and ischemic events as stent thrombosis or cardiovascular death was found. However, recent large scale randomized, controlled trials have consistently failed to demonstrate a benefit of personalised antiplatelet therapy based on platelet function testing.
Journal Article
Contractile forces in platelet aggregates under microfluidic shear gradients reflect platelet inhibition and bleeding risk
Platelets contract forcefully after their activation, contributing to the strength and stability of platelet aggregates and fibrin clots during blood coagulation. Viscoelastic approaches can be used to assess platelet-induced clot strengthening, but they require thrombin and fibrin generation and are unable to measure platelet forces directly. Here, we report a rapid, microfluidic approach for measuring the contractile force of platelet aggregates for the detection of platelet dysfunction. We find that platelet forces are significantly reduced when blood samples are treated with inhibitors of myosin, GPIb-IX-V, integrin α
IIb
β
3,
P2Y
12
, or thromboxane generation. Clinically, we find that platelet forces are measurably lower in cardiology patients taking aspirin. We also find that measuring platelet forces can identify Emergency Department trauma patients who subsequently require blood transfusions. Together, these findings indicate that microfluidic quantification of platelet forces may be a rapid and useful approach for monitoring both antiplatelet therapy and traumatic bleeding risk.
Platelet aggregates generate contractile forces that contribute to their cohesion and adhesion. Here, Ting et al. develop a microfluidic device to measure contractile forces generated by platelet aggregates, and find it can detect the response of platelets to pharmacological agents and predict bleeding risk in trauma patients.
Journal Article
Advancing Platelet Research Through Live-Cell Imaging: Challenges, Techniques, and Insights
Platelet cells are essential to maintain haemostasis and play a critical role in thrombosis. They swiftly respond to vascular injury by adhering to damaged vessel surfaces, activating signalling pathways, and aggregating with each other to control bleeding. This dynamic process of platelet activation is intricately coordinated, spanning from membrane receptor maturation to intracellular interactions to whole-cell responses. Live-cell imaging has become an invaluable tool for dissecting these complexes. Despite its benefits, live imaging of platelets presents significant technical challenges. This review addresses these challenges, identifying key areas in need of further development and proposing possible solutions. We also focus on the dynamic processes of platelet adhesion, activation, and aggregation in haemostasis and thrombosis, applying imaging capacities from the microscale to the nanoscale. By exploring various live imaging techniques, we demonstrate how these approaches offer crucial insights into platelet biology and deepen our understanding of these three core events. In conclusion, this review provides an overview of the imaging methods currently available for studying platelet dynamics, guiding researchers in selecting suitable techniques for specific studies. By advancing our knowledge of platelet behaviour, these imaging methods contribute to research on haemostasis, thrombosis, and platelet-related diseases, ultimately aiming to improve clinical outcomes.
Journal Article
Platelet biology and functions: new concepts and clinical perspectives
Platelets — blood cells continuously produced from megakaryocytes mainly in the bone marrow — are implicated not only in haemostasis and arterial thrombosis, but also in other physiological and pathophysiological processes. This Review describes current evidence for the heterogeneity in platelet structure, age, and activation properties, with consequences for a diversity of platelet functions. Signalling processes of platelet populations involved in thrombus formation with ongoing coagulation are well understood. Genetic approaches have provided information on multiple genes related to normal haemostasis, such as those encoding receptors and signalling or secretory proteins, that determine platelet count and/or responsiveness. As highly responsive and secretory cells, platelets can alter the environment through the release of growth factors, chemokines, coagulant factors, RNA species, and extracellular vesicles. Conversely, platelets will also adapt to their environment. In disease states, platelets can be positively primed to reach a pre-activated condition. At the inflamed vessel wall, platelets interact with leukocytes and the coagulation system, interactions mediating thromboinflammation. With current antiplatelet therapies invariably causing bleeding as an undesired adverse effect, novel therapies can be more beneficial if directed against specific platelet responses, populations, interactions, or priming conditions. On the basis of these novel concepts and processes, we discuss several initiatives to target platelets therapeutically.
Journal Article
GPVI-dependent functional competence of buffy coat platelet concentrates (PCs) versus PRP-derived PCs: insights into the effects of biomechanical forces during platelet preparation
Platelet isolation is a decisive stage in the preparation of platelet concentrate (PC), which may affect functional competence of platelets during storage and post-transfusion. Now considering GPVI as a vulnerable receptor that is mainly affected by shear stress and redox state, this study was conducted for the first time to compare preparation methods of Buffy Coat (BC)- and Platelet-Rich Plasma (PRP)-PCs in terms of GPVI-related phenotypic and functional status. BC- and PRP-PCs were subjected to flow cytometry to analyze GPVI expression and intra-platelet ROS generation. Soluble GPVI were determined by ELISA. Platelet aggregation response to collagen and its adhesion to the collagen matrix were examined by aggregometry and fluorescence microscope, respectively. All the parameters were analyzed on days 0, 1, 3, and 5 of storage. Stored-dependent ROS generation showed significantly higher levels in PRP-PCs compared to BC-PCs on days 1 and 3 of storage. GPVI expression decreased in both products, with BC-PCs showing higher levels on 1 and 3 days of storage. However, with a similar trend, PRP-PCs showed higher levels of shedding, which was significant on day 3. Adhesion/spreading to the collagen matrix also decreased during storage, with higher declines observed in PRP-PCs. Platelet aggregation showed the same pattern with significantly lower PRP-PCs responses to collagen than BC-PCs on the third and fifth days of storage. During platelet storage, GPVI-dependent platelet functional capacity in BC-PCs was better preserved than PRP-PCs, suggesting the priority of BC-PCs method for platelet preparation. In this regard, adopting methods such as platelet isolation and storage in optimal additive solutions, especially those containing ROS scavengers, may help maintain the integrity of GPVI in PRP products. However, further studies, particularly using animal models of thrombus formation, are needed to determine whether the enhanced GPVI function in BC-PCs compared with PRP-PCs can translate into superior efficacy after blood transfusion.
Research highlights
Platelet concentrates (PCs) are technically separated from platelet-rich plasma (PRP) or buffy coat (BC) of whole blood.
ROS showed significantly higher levels in PRP-PCs compared to BC-one on days 1 and 3 of storage.
BC-PCs showed higher levels of GPVI expression compared to PRP-PCs on days 1 and 3 of storage.
PRP-PCs showed higher levels of GPVI shedding compared to BC-PCs, with the significance at day 3 of storage.
The response of PRP-PCs to collagen was lower than BC-PCs on days 3 and 5 of storage.
GPVI-dependent platelet functional capacity in BC-PCs was better preserved than in PRP-PCs during storage.
Journal Article
Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation
Significance Platelets are cell fragments in the blood that initiate clot formation at the site of bleeding. Although the biological aspects of this process have been well characterized, whether platelets can detect and physiologically respond to the mechanical aspects of its local environment is unclear. Here, we show that platelets sense the stiffness of the underlying clot substrate, and increasing substrate stiffness increases platelet adhesion and spreading. Importantly, adhesion on stiffer substrates leads to higher levels of platelet activation. Mechanistically, we determined that Rac1, actin, and myosin activity mediate this process. This newfound capability of how platelets adjust their degree of activation based on the mechanical properties of their environment provides new insight into how clots are formed.
As platelets aggregate and activate at the site of vascular injury to stem bleeding, they are subjected to a myriad of biochemical and biophysical signals and cues. As clot formation ensues, platelets interact with polymerizing fibrin scaffolds, exposing platelets to a large range of mechanical microenvironments. Here, we show for the first time (to our knowledge) that platelets, which are anucleate cellular fragments, sense microenvironmental mechanical properties, such as substrate stiffness, and transduce those cues into differential biological signals. Specifically, as platelets mechanosense the stiffness of the underlying fibrin/fibrinogen substrate, increasing substrate stiffness leads to increased platelet adhesion and spreading. Importantly, adhesion on stiffer substrates also leads to higher levels of platelet activation, as measured by integrin α IIbβ ₃ activation, α-granule secretion, and procoagulant activity. Mechanistically, we determined that Rac1 and actomyosin activity mediate substrate stiffness-dependent platelet adhesion, spreading, and activation to different degrees. This capability of platelets to mechanosense microenvironmental cues in a growing thrombus or hemostatic plug and then mechanotransduce those cues into differential levels of platelet adhesion, spreading, and activation provides biophysical insight into the underlying mechanisms of platelet aggregation and platelet activation heterogeneity during thrombus formation.
Journal Article
Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting
Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin.
Journal Article
Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting
Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.
Journal Article