Platelet‐based coagulation: different populations, different functions

Heemskerk, Johan W. M.; Mattheij, Nadine J.A.; Cosemans, Judith M.E.M.

doi:10.1111/jth.12045

Cited by 293 publications

(312 citation statements)

References 160 publications

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“…1,2 In a growing thrombus, aggregated and procoagulant platelets form two distinct populations, 3,4 which is at least partly explained by the high Ca 2+ response required for PS exposure and coagulation factor binding, and by the calpain-dependent closure of active α IIb b 3 integrins after PS exposure, thus antagonizing inclusion of procoagulant platelets into a platelet aggregate. 5,6 However, another platelet population has also been identified, usually referred to as coated platelets, 7 which may partly overlap with the two other platelet populations described above. 3 In the initial paper, Dale et al describe COAT platelets (later renamed as coated platelets) as a population of platelets arising after combined stimulation with collagen and thrombin, which bind α-granule proteins, including factor V, fibrinogen, von Willebrand factor, thrombospondin, fibronectin and α 2 -antiplasmin, in a transglutaminase-dependent way via the formation of covalent serotonin conjugations.…”

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confidence: 99%

Coated platelets function in platelet-dependent fibrin formation via integrin α _IIb β ₃ and transglutaminase factor XIII

et al. 2015

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C oated platelets, formed by collagen and thrombin activation, have been characterized in different ways: i) by the formation of a protein coat of α-granular proteins; ii) by exposure of procoagulant phosphatidylserine; or iii) by high fibrinogen binding. Yet, their functional role has remained unclear. Here we used a novel transglutaminase probe, Rhod-A14, to identify a subpopulation of platelets with a cross-linked protein coat, and compared this with other platelet subpopulations using a panel of functional assays. Platelet stimulation with convulxin/thrombin resulted in initial integrin α IIb b 3 activation, the appearance of a platelet population with high fibrinogen binding, (independently of active integrins, but dependent on the presence of thrombin) followed by phosphatidylserine exposure and binding of coagulation factors Va and Xa. A subpopulation of phosphatidylserine-exposing platelets bound Rhod-A14 both in suspension and in thrombi generated on a collagen surface. In suspension, high fibrinogen and Rhod-A14 binding were antagonized by combined inhibition of transglutaminase activity and integrin α IIb b 3 . Markedly, in thrombi from mice deficient in transglutaminase factor XIII, platelet-driven fibrin formation and Rhod-A14 binding were abolished by blockage of integrin α IIb b 3 . Vice versa, star-like fibrin formation from platelets of a patient with deficiency in α IIb b 3 (Glanzmann thrombasthenia) was abolished upon blockage of transglutaminase activity. We conclude that coated platelets, with initial α IIb b 3 activation and high fibrinogen binding, form a subpopulation of phosphatidylserine-exposing platelets, and function in platelet-dependent star-like fibrin fiber formation via transglutaminase factor XIII and integrin α IIb b 3 .

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confidence: 99%

Coated platelets function in platelet-dependent fibrin formation via integrin α _IIb β ₃ and transglutaminase factor XIII

et al. 2015

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“…factor V, thrombospondin, fibronectin, von Willebrand factor) bind to these platelets in an ␣ IIb ␤ 3 -independent way via transglutaminase activity. Procoagulant and coated platelets represent two not completely overlapping populations, as not all PS-exposing platelets display high fibrinogen binding (2). In the present study, we investigated the mechanism of integrin ␣ IIb ␤ 3 inactivation in procoagulant platelets by determining the functional roles of calpain, Src-dependent signaling, TMEM16F, and mPTP formation.…”

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confidence: 99%

“…Under thrombotic conditions in flowing blood, ␣ IIb ␤ 3 -dependent platelet aggregation mediates thrombus formation and, finally, occlusion of a damaged cardiac or carotid artery (1). Microscopic observations have shown that both in vivo and in parallel-plate flow chambers, the aggregated platelets in a thrombus are surrounded by patches of procoagulant platelets with quite distinct properties (2). The latter platelets characteristically are elevated in cytosolic Ca 2ϩ , have a rounded morphology with attached microparticles, and expose the negatively charged lipid, phosphatidylserine (PS).…”

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confidence: 99%

Dual Mechanism of Integrin αIIbβ3 Closure in Procoagulant Platelets

Mattheij

Gilio

Kruchten

et al. 2013

Journal of Biological Chemistry

101

156

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Background: Inactivation of integrin ␣ IIb ␤ 3 reverses platelet aggregate formation upon coagulation. Results and conclusion: Platelets from patient (Scott) and mouse (Capn1 Ϫ/Ϫ and Ppif Ϫ/Ϫ ) blood reveal a dual mechanism of ␣ IIb ␤ 3 inactivation: by calpain-2 cleavage of integrin-associated proteins and by cyclophilin D/TMEM16F-dependent phospholipid scrambling. Significance: These data provide novel insight into the switch mechanisms from aggregating to procoagulant platelets.

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“…In addition, the actual age of the platelets may affect their responsiveness (102). The platelets role in the coagulation related to their surface properties is also contributing to the heterogeneous content (103).…”

Section: The Heterogeneous Thrombusmentioning

confidence: 99%

“…In paper 3 we described the movement of two platelet subgroups, platelet labelled with a platelet-specific antibody and platelets that were positive for Annexin V, platelets that expose phosphatidylserine (PS). Platelets exposing PS is essential for a full coagulation response, Annexin V will hinder the coagulation factors from binding to the surface and thereby hinder coagulation (103). It was, therefore, the reason not to introduce coagulation in that setting of paper 3.…”

Section: Shear Rate and Anticoagulantsmentioning

confidence: 99%

Counting and Tracking: Development and Use of New Methods for Detailed Analysis of Thrombus Formation

Tunströmer¹

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Blood platelets are a part of the complex system called haemostasis aimed at ensuring our blood's continuous transport of oxygen and nutrients throughout the body. The transport is ensured by limiting blood loss due to vessel injury and in this process, the platelets form a plug in the damaged area, reinforced by the formation of fibrin. Similar mechanisms may cause thrombus formation, often triggered by atherosclerotic plaque rupture, causing vessel occlusion, embolism or ischemia, which may cause irreversible damage to the heart or the brain.Platelet research is crucial for improved prevention and treatment of thrombotic disorders. For such research, flow chambers are an interesting tool for studies of platelet adhesion, aggregation and thrombus formation under similar flow conditions as in the blood vessels, which is important, as the flow affects the mechanisms involved in both haemostasis and thrombosis. Flow chambers can be designed for specific purposes, such as for the study of haemostasis at specific flow conditions or to evaluate drugs or biomaterials. In this thesis, our aim has been to improve the usefulness of in-vitro flow chambers and develop a more robust and informative image analysis of such experiments.Initially, we introduced an internal control within each flow chamber experiment, thereby reducing the experimental variance caused by unknown factors. Furthermore, control and sample were thus exposed to identical experimental settings. By using platelet count as quantification of thrombus formation we introduce a method of analysis with increased or similar sensitivity to today's standards. The platelet count method facilitated comparison of results obtained in different types of flow chambers by an absolute scale of measurement, independent of user settings. The platelet count method was further developed so that additional parameters could be analysed, providing more information about each individual platelet and the overall thrombus. The parameters analysed included platelet stability, height, movement and contraction. The method was used to evaluate how the pharmacokinetics of a reversible (ticagrelor) and irreversible (prasugrel) platelet ADP-receptor inhibitor affected the overall thrombus formation. Especially, how a non-inhibited platelet fraction, formed between drug administrations of irreversible inhibitors, affected thrombus formation. In addition, we sought to understand the regulation of the thrombin receptor, PAR1, expression in cancer cells. We found the microRNA miR20b to be antioncogenic through its downregulation of PAR1 expression.This thesis contains numerous flow chamber experiments. However, for further use and full potential of the method increased standardisation is important. Our work regarding the quantification and analysis of flow chamber experiments will contribute to a more robust analysis and maybe even more important, provide new and detailed information on thrombus formation. Populärvetenskaplig sammanfattningVåra celler är i konstant behov av syre och...

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Platelet‐based coagulation: different populations, different functions

Cited by 293 publications

References 160 publications

Coated platelets function in platelet-dependent fibrin formation via integrin α _IIb β ₃ and transglutaminase factor XIII

Coated platelets function in platelet-dependent fibrin formation via integrin α _IIb β ₃ and transglutaminase factor XIII

Dual Mechanism of Integrin αIIbβ3 Closure in Procoagulant Platelets

Counting and Tracking: Development and Use of New Methods for Detailed Analysis of Thrombus Formation

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Platelet‐based coagulation: different populations, different functions

Cited by 293 publications

References 160 publications

Coated platelets function in platelet-dependent fibrin formation via integrin α IIb β 3 and transglutaminase factor XIII

Coated platelets function in platelet-dependent fibrin formation via integrin α IIb β 3 and transglutaminase factor XIII

Dual Mechanism of Integrin αIIbβ3 Closure in Procoagulant Platelets

Counting and Tracking: Development and Use of New Methods for Detailed Analysis of Thrombus Formation

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Product

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Coated platelets function in platelet-dependent fibrin formation via integrin α _IIb β ₃ and transglutaminase factor XIII

Coated platelets function in platelet-dependent fibrin formation via integrin α _IIb β ₃ and transglutaminase factor XIII