Chronic expression of platelet adhesion proteins is associated with severe ischemic heart disease in type 2 diabetic patients
Paul F. McDonaghJason Y HokamaStephen C. GaleJeremy J LoganGrace Davis‐GormanSteve GoldmanJack G. Copeland
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P-selectin
Pathophysiology
Platelet adhesiveness
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Abstract Background Patients with coronavirus disease-19 (COVID-19) are at increased risk of thrombosis, which is associated with altered platelet function and coagulopathy, contributing to excess mortality. Objectives We aimed to characterise the mechanism of altered platelet function in COVID-19 patients. Methods The platelet proteome, platelet functional responses and platelet-neutrophil aggregates were compared between patients hospitalised with COVID-19 and healthy control subjects using Tandem Mass Tag (TMT) proteomic analysis, Western blotting and flow cytometry. Results COVID-19 patients showed a different profile of platelet protein expression (858 altered out of 5773 quantified). Levels of COVID-19 plasma markers were enhanced in COVID-19 platelets. Gene ontology (GO) pathway analysis demonstrated that levels of granule secretory proteins were raised, whereas some platelet activation proteins, such as the thrombopoietin receptor and PKCα, were lowered. Basally, COVID-19 platelets showed enhanced phosphatidylserine (PS) exposure, with unaltered integrin α IIb β 3 activation and P-selectin expression. Agonist-stimulated integrin α IIb β 3 activation and PS exposure, but not P-selectin expression, were significantly decreased in COVID-19 patients. COVID-19 patients had high levels of platelet-neutrophil aggregates, even under basal conditions, compared to controls. This interaction was disrupted by blocking P-selectin, demonstrating that platelet P-selectin is critical for the interaction. Conclusions Overall, our data suggests the presence of two platelet populations in patients with COVID-19: one with circulating platelets with an altered proteome and reduced functional responses and another with P-selectin expressing neutrophil-associated platelets. Platelet driven thromboinflammation may therefore be one of the key factors enhancing the risk of thrombosis in COVID-19 patients. Essentials - COVID-19 patient platelet function and platelet proteins were compared with healthy controls - Proteomic analysis of platelets indicated that COVID-19 decreased platelet activation proteins - Agonist induced PS exposure and integrin α IIb β 3 activation were impaired in COVID-19 - COVID-19 led to maximal levels of P-selectin dependent platelet-neutrophil aggregates
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Abstract Introduction The contribution of platelets in thrombosis within microcirculation has been extensively documented in the literature. We previously showed, in vivo, that platelet activation revealed by intracellular calcium mobilization was a crucial step in the growth of thrombi following laser-induced injury, a model of thromboinflammation. Aim We employed a multimodal, correlative microscopy approach and computational biology to investigate the extent of platelet activation and the spatial distribution of platelets throughout a growing thrombus. Results We observed a reversible intracellular platelet calcium mobilization that correlates with the time a platelet resides during thrombus growth. Our bioinformatics analysis displayed three distinct platelet subpopulations resident within a thrombus: (1) resting, (2) partially activated, and (3) “fully” activated platelets. The spatial distribution of the platelet subpopulations in the thrombus creates a double gradient in both the transversal and longitudinal axis, with the maximal percentage of fully activated platelets close to the site of injury. However, these activated platelets did not express negative phospholipids. The injured endothelium was identified to play a vital role in activating the blood coagulation cascade in this model of thrombosis. Conclusion Following a laser-induced injury, thrombi are formed by a gradient of activated platelets from the injury site to the periphery of the thrombus. These different activation states of platelets throughout the thrombi regulate the biomechanics of the thrombus. The injured endothelium, rather than platelets, was identified to play a key role in the activation of the blood coagulation cascade in this model of thromboinflammation. Essentials Computational biology was used to analyze thrombosis. Non-activated, low- and fully-activated platelets are part of a thrombus. The activation of the platelets forms a gradient from the site of injury to the periphery. The endothelium, and not platelets, expressed negative phospholipids. Graphical abstract A thrombus is formed by a gradient of platelet activation and procoagulant endothelium
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By using two distinct measurements of alpha‐degranulation (surface P‐ selectin [alpha‐granule membrane protein‐140] expression and beta‐ thromboglobulin [beta‐TG] release) and quantitation of glycoprotein (GP) IIb/IIIa surface density, stored platelet concentrates were evaluated to determine a) which method of measuring platelet alpha‐ granule release was more sensitive in detecting early platelet activation; b) whether Day 1 levels of activation predicted the extent of activation or cell lysis on Day 5 of storage; and c) whether changes in surface GPIIb/IIIa density were primarily dependent on platelet activation. By using samples from paired and unpaired units stored for 1, 3, and 5 days, four observations could be made. 1) A flow cytometric assay for the percentage of P‐selectin‐positive platelets was more sensitive for early detection of platelet activation than was measurement of beta‐TG release. This finding was most likely due to enhanced sensitivity in detecting platelets that had undergone partial alpha‐granule release. 2) Total P‐selectin expression correlated with beta‐TG release, which indicated that the extent of alpha‐granule membrane fusion with the external platelet membrane was proportional to the amount of alpha‐granule contents released into the supernatant. 3) All of the activation measurements on Day 1 predicted the activation values, but did not predict the degree of cell lysis (measured by lactate dehydrogenase discharge), on Day 5 of storage. 4) Surface GPIIb/IIIa density was increased on the subset of P‐selectin‐positive platelets as compared with the P‐selectin‐negative subset at all times during storage, but, within each subset, GPIIb/IIIa surface density did not significantly increase over the time of storage.
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Beta-thromboglobulin
Granule (geology)
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Background and Objectives: Hyperconcentration of platelets may lead to platelet activation and loss of platelet function. Materials and Methods: Platelet activation following hyperconcentration was assessed using flow-cytometric detection of platelet P-selectin expression and platelet swirling. Results: Platelet hyperconcentration led to a minimal increase in P-selectin expression and no differnce in platelet swirling. Conclusion: Hyperconcentration was not associated with a clinically significant change in platelet activation and had no significant effect on platelet quality as detected by pH and platelet yield.
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Radionuclide imaging of platelet activation in thrombus can display thrombus and discriminate the fresh thrombus from old ones.The mechanism of platelet activation and the progress of radionuclide imaging of platelet activation in thrombus were reviewed in this article.
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Cremaster muscle
Intravital microscopy
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