Platelet Membrane Receptor Proteolysis: Implications for Platelet Function

Wu, Jiayu; Heemskerk, Johan W. M.; Baaten, Constance C. F. M. J.

doi:10.3389/fcvm.2020.608391

Cited by 23 publications

(27 citation statements)

References 141 publications

(183 reference statements)

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“…The serine protease thrombin cleaves coagulation factors, producing fibrin fibres from fibrinogen, and it also cleaves platelet protease-activated receptors (PARs) [76,77]. On human platelets, thrombin cleaves and activates the Gαq-protein-coupled receptors PAR1/4, while thrombin has an additional minor stimulatory role through its binding to the GPIb-V-IX complex [78].…”

Section: Thrombin and Protease-activated Receptors (Par1 Par4)mentioning

confidence: 99%

“…On human platelets, thrombin cleaves and activates the Gαq-protein-coupled receptors PAR1/4, while thrombin has an additional minor stimulatory role through its binding to the GPIb-V-IX complex [78]. PAR1 is the receptor operating at low thrombin concentrations, while PAR4 becomes activated at higher agonist concentrations [77]. The classical Gαq pathway leads to activation of phospholipase Cβ (PLCβ), which like PLCγ2 hydrolyses phosphatidylinositol 4,5-bisphosphate into the second messengers inositol trisphosphate (IP 3 ) and diacylglycerol [5].…”

Section: Thrombin and Protease-activated Receptors (Par1 Par4)mentioning

confidence: 99%

“…After activation or ageing, platelets lose part of their constituents to the environment in several ways, i.e., by granular secretion, extracellular vesicle (microparticle) formation and receptor shedding [77]. Together, the lost proteins are termed as the releasate proteome [83].…”

Section: Thrombin and Protease-activated Receptors (Par1 Par4)mentioning

confidence: 99%

See 2 more Smart Citations

Molecular Proteomics and Signalling of Human Platelets in Health and Disease

Huang

Zhang

Solari

et al. 2021

IJMS

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Platelets are small anucleate blood cells that play vital roles in haemostasis and thrombosis, besides other physiological and pathophysiological processes. These roles are tightly regulated by a complex network of signalling pathways. Mass spectrometry-based proteomic techniques are contributing not only to the identification and quantification of new platelet proteins, but also reveal post-translational modifications of these molecules, such as acetylation, glycosylation and phosphorylation. Moreover, target proteomic analysis of platelets can provide molecular biomarkers for genetic aberrations with established or non-established links to platelet dysfunctions. In this report, we review 67 reports regarding platelet proteomic analysis and signalling on a molecular base. Collectively, these provide detailed insight into the: (i) technical developments and limitations of the assessment of platelet (sub)proteomes; (ii) molecular protein changes upon ageing of platelets; (iii) complexity of platelet signalling pathways and functions in response to collagen, rhodocytin, thrombin, thromboxane A2 and ADP; (iv) proteomic effects of endothelial-derived mediators such as prostacyclin and the anti-platelet drug aspirin; and (v) molecular protein changes in platelets from patients with congenital disorders or cardiovascular disease. However, sample sizes are still low and the roles of differentially expressed proteins are often unknown. Based on the practical and technical possibilities and limitations, we provide a perspective for further improvements of the platelet proteomic field.

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Section: Thrombin and Protease-activated Receptors (Par1 Par4)mentioning

confidence: 99%

Section: Thrombin and Protease-activated Receptors (Par1 Par4)mentioning

confidence: 99%

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Molecular Proteomics and Signalling of Human Platelets in Health and Disease

Huang

Zhang

Solari

et al. 2021

IJMS

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“…In addition to the release of soluble proteins from granules, proteolytic cleavage of platelet membrane proteins occurs mainly by metalloproteinases (MMP) and the shed fragments can modulate cellular responses. The platelet sheddome, excluding plasma proteins and platelet-derived extracellular vesicles, contains at least 69 membrane proteins (21,22). Only a fraction of all membrane proteins is cleaved, among these are the externalized surface proteins P-selectin and CD40L, the receptor GPIbα, GPV subunits of the GPIb-IX-V complex, and GPVI (21,(23)(24)(25).…”

Section: Platelet Release Factorsmentioning

confidence: 99%

Soluble Platelet Release Factors as Biomarkers for Cardiovascular Disease

Baidildinova

Nagy

Jurk

et al. 2021

Front. Cardiovasc. Med.

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Platelets are the main players in thrombotic diseases, where activated platelets not only mediate thrombus formation but also are involved in multiple interactions with vascular cells, inflammatory components, and the coagulation system. Although in vitro reactivity of platelets provides information on the function of circulating platelets, it is not a full reflection of the in vivo activation state, which may be relevant for thrombotic risk assessment in various disease conditions. Therefore, studying release markers of activated platelets in plasma is of interest. While this type of study has been done for decades, there are several new discoveries that highlight the need for a critical assessment of the available tests and indications for platelet release products. First, new insights have shown that platelets are not only prominent players in arterial vascular disease, but also in venous thromboembolism and atrial fibrillation. Second, knowledge of the platelet proteome has dramatically expanded over the past years, which contributed to an increasing array of tests for proteins released and shed from platelets upon activation. Identification of changes in the level of plasma biomarkers associated with upcoming thromboembolic events allows timely and individualized adjustment of the treatment strategy to prevent disease aggravation. Therefore, biomarkers of platelet activation may become a valuable instrument for acute event prognosis. In this narrative review based on a systematic search of the literature, we summarize the process of platelet activation and release products, discuss the clinical context in which platelet release products have been measured as well as the potential clinical relevance.

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“…In this pathway, locally formed thrombin binds to endothelial‐expressed thrombomodulin (TM), which complex activates protein C on the endothelial protein C receptor 13 . Protein S herein acts as a cofactor, supporting the role of activated protein C (APC) to inactivate the coagulation process 14,15 16 …”

Section: Introductionmentioning

confidence: 99%

Protein C or Protein S deficiency associates with paradoxically impaired platelet‐dependent thrombus and fibrin formation under flow

Brouns

Tullemans

Bulato

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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Background Low plasma levels of protein C or protein S are associated with venous thromboembolism rather than myocardial infarction. The high coagulant activity in patients with thrombophilia with a (familial) defect in protein C or S is explained by defective protein C activation, involving thrombomodulin and protein S. This causes increased plasmatic thrombin generation. Objective Assess the role of platelets in the thrombus‐ and fibrin‐forming potential in patients with familial protein C or protein S deficiency under high‐shear flow conditions. Patients/Methods Whole blood from 23 patients and 15 control subjects was perfused over six glycoprotein VI–dependent microspot surfaces. By real‐time multicolor microscopic imaging, kinetics of platelet thrombus and fibrin formation were characterized in 49 parameters. Results and Conclusion Whole‐blood flow perfusion over collagen, collagen‐like peptide, and fibrin surfaces with low or high GPVI dependency indicated an unexpected impairment of platelet activation, thrombus phenotype, and fibrin formation but unchanged platelet adhesion, observed in patients with protein C deficiency and to a lesser extent protein S deficiency, when compared to controls. The defect extended from diminished phosphatidylserine exposure and thrombus contraction to delayed and suppressed fibrin formation. The mechanism was thrombomodulin independent, and may involve negative platelet priming by plasma components.

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Platelet Membrane Receptor Proteolysis: Implications for Platelet Function

Cited by 23 publications

References 141 publications

Molecular Proteomics and Signalling of Human Platelets in Health and Disease

Molecular Proteomics and Signalling of Human Platelets in Health and Disease

Soluble Platelet Release Factors as Biomarkers for Cardiovascular Disease

Protein C or Protein S deficiency associates with paradoxically impaired platelet‐dependent thrombus and fibrin formation under flow

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