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20 pages, 3704 KiB

Open AccessArticle

Role of Platelet Glycoprotein VI and Tyrosine Kinase Syk in Thrombus Formation on Collagen-Like Surfaces

by Natalie J. Jooss, Ilaria De Simone, Isabella Provenzale, Delia I. Fernández, Sanne L.N. Brouns, Richard W. Farndale, Yvonne M.C. Henskens, Marijke J.E. Kuijpers, Hugo ten Cate, Paola E.J. van der Meijden, Rachel Cavill and Johan W.M. Heemskerk

Int. J. Mol. Sci. 2019, 20(11), 2788; https://doi.org/10.3390/ijms20112788 - 07 Jun 2019

Cited by 28 | Viewed by 4379

Abstract

Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α₂β₁. Protein tyrosine kinase Syk is central in the [...] Read more.

Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α₂β₁. Protein tyrosine kinase Syk is central in the GPVI-induced signaling pathway, leading to elevated cytosolic Ca²⁺. We aimed to determine the Syk-mediated thrombogenic activity of several collagen peptides and (fibrillar) type I and III collagens. High-shear perfusion of blood over microspots of these substances resulted in thrombus formation, which was assessed by eight parameters and was indicative of platelet adhesion, activation, aggregation, and contraction, which were affected by the Syk inhibitor PRT-060318. In platelet suspensions, only collagen peptides containing the consensus GPVI-activating sequence (GPO)_n and Horm-type collagen evoked Syk-dependent Ca²⁺ rises. In whole blood under flow, Syk inhibition suppressed platelet activation and aggregation parameters for the collagen peptides with or without a (GPO)_n sequence and for all of the collagens. Prediction models based on a regression analysis indicated a mixed role of GPVI in thrombus formation on fibrillar collagens, which was abolished by Syk inhibition. Together, these findings indicate that GPVI-dependent signaling through Syk supports platelet activation in thrombus formation on collagen-like structures regardless of the presence of a (GPO)_n sequence. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

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Review

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14 pages, 342 KiB

Open AccessReview

Primary Hemostasis in Chronic Liver Disease and Cirrhosis: What Did We Learn over the Past Decade?

by Marie-Astrid van Dievoet, Stéphane Eeckhoudt and Xavier Stephenne

Int. J. Mol. Sci. 2020, 21(9), 3294; https://doi.org/10.3390/ijms21093294 - 06 May 2020

Cited by 11 | Viewed by 3245

Abstract

Changes in primary hemostasis have been described in patients with chronic liver disease (CLD) and cirrhosis and are still subject to ongoing debate. Thrombocytopenia is common and multifactorial. Numerous studies also reported platelet dysfunction. In spite of these changes, primary hemostasis seems to [...] Read more.

Changes in primary hemostasis have been described in patients with chronic liver disease (CLD) and cirrhosis and are still subject to ongoing debate. Thrombocytopenia is common and multifactorial. Numerous studies also reported platelet dysfunction. In spite of these changes, primary hemostasis seems to be balanced. Patients with CLD and cirrhosis can suffer from both hemorrhagic and thrombotic complications. Variceal bleeding is the major hemorrhagic complication and is mainly determined by high portal pressure. Non portal hypertension-related bleeding due to hemostatic failure is uncommon. Thrombocytopenia can complicate management of invasive procedures in CLD patients. Recently, oral thrombopoietin agonists have been approved to raise platelets before invasive procedures. In this review we aim to bundle literature, published over the past decade, discussing primary hemostasis in CLD and cirrhosis including (1) platelet count and the role of thrombopoietin (TPO) agonists, (2) platelet function tests and markers of platelet activation, (3) von Willebrand factor and (4) global hemostasis tests. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

25 pages, 1099 KiB

Open AccessReview

P2Y₁₂ Inhibition beyond Thrombosis: Effects on Inflammation

by Alexandre Mansour, Christilla Bachelot-Loza, Nicolas Nesseler, Pascale Gaussem and Isabelle Gouin-Thibault

Int. J. Mol. Sci. 2020, 21(4), 1391; https://doi.org/10.3390/ijms21041391 - 19 Feb 2020

Cited by 65 | Viewed by 9463

Abstract

The P2Y₁₂ receptor is a key player in platelet activation and a major target for antithrombotic drugs. The beneficial effects of P2Y₁₂ receptor antagonists might, however, not be restricted to the primary and secondary prevention of arterial thrombosis. Indeed, it has [...] Read more.

The P2Y₁₂ receptor is a key player in platelet activation and a major target for antithrombotic drugs. The beneficial effects of P2Y₁₂ receptor antagonists might, however, not be restricted to the primary and secondary prevention of arterial thrombosis. Indeed, it has been established that platelet activation also has an essential role in inflammation. Additionally, nonplatelet P2Y₁₂ receptors present in immune cells and vascular smooth muscle cells might be effective players in the inflammatory response. This review will investigate the biological and clinical impact of P2Y₁₂ receptor inhibition beyond its platelet-driven antithrombotic effects, focusing on its anti-inflammatory role. We will discuss the potential molecular and cellular mechanisms of P2Y₁₂-mediated inflammation, including cytokine release, platelet–leukocyte interactions and neutrophil extracellular trap formation. Then we will summarize the current evidence on the beneficial effects of P2Y₁₂ antagonists during various clinical inflammatory diseases, especially during sepsis, acute lung injury, asthma, atherosclerosis, and cancer. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

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15 pages, 1612 KiB

Open AccessReview

Platelet Biochemistry and Morphology after Cryopreservation

by Katrijn R. Six, Veerle Compernolle and Hendrik B. Feys

Int. J. Mol. Sci. 2020, 21(3), 935; https://doi.org/10.3390/ijms21030935 - 31 Jan 2020

Cited by 15 | Viewed by 11340

Abstract

Platelet cryopreservation has been investigated for several decades as an alternative to room temperature storage of platelet concentrates. The use of dimethylsulfoxide as a cryoprotectant has improved platelet storage and cryopreserved concentrates can be kept at −80 °C for two years. Cryopreserved platelets [...] Read more.

Platelet cryopreservation has been investigated for several decades as an alternative to room temperature storage of platelet concentrates. The use of dimethylsulfoxide as a cryoprotectant has improved platelet storage and cryopreserved concentrates can be kept at −80 °C for two years. Cryopreserved platelets can serve as emergency backup to support stock crises or to disburden difficult logistic areas like rural or military regions. Cryopreservation significantly influences platelet morphology, decreases platelet activation and severely abrogates platelet aggregation. Recent data indicate that cryopreserved platelets have a procoagulant phenotype because thrombin and fibrin formation kicks in earlier compared to room temperature stored platelets. This happens both in static and hydrodynamic conditions. In a clinical setting, low 1-h post transfusion recoveries of cryopreserved platelets represent fast clearance from circulation which may be explained by changes to the platelet GPIbα receptor. Cryopreservation splits the concentrate in two platelet subpopulations depending on GPIbα expression levels. Further research is needed to unravel its physiological importance. Proving clinical efficacy of cryopreserved platelets is difficult because of the heterogeneity of indications and the ambiguity of outcome measures. The procoagulant character of cryopreserved platelets has increased interest for use in trauma stressing the need for double-blinded randomized clinical trials in actively bleeding patients. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

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27 pages, 2935 KiB

Open AccessReview

Coagulatory Defects in Type-1 and Type-2 Diabetes

by Amélie I. S. Sobczak and Alan J. Stewart

Int. J. Mol. Sci. 2019, 20(24), 6345; https://doi.org/10.3390/ijms20246345 - 16 Dec 2019

Cited by 49 | Viewed by 8580

Abstract

Diabetes (both type-1 and type-2) affects millions of individuals worldwide. A major cause of death for individuals with diabetes is cardiovascular diseases, in part since both types of diabetes lead to physiological changes that affect haemostasis. Those changes include altered concentrations of coagulatory [...] Read more.

Diabetes (both type-1 and type-2) affects millions of individuals worldwide. A major cause of death for individuals with diabetes is cardiovascular diseases, in part since both types of diabetes lead to physiological changes that affect haemostasis. Those changes include altered concentrations of coagulatory proteins, hyper-activation of platelets, changes in metal ion homeostasis, alterations in lipid metabolism (leading to lipotoxicity in the heart and atherosclerosis), the presence of pro-coagulatory microparticles and endothelial dysfunction. In this review, we explore the different mechanisms by which diabetes leads to an increased risk of developing coagulatory disorders and how this differs between type-1 and type-2 diabetes. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

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16 pages, 1998 KiB

Open AccessReview

Zinc Homeostasis in Platelet-Related Diseases

by Elmina Mammadova-Bach and Attila Braun

Int. J. Mol. Sci. 2019, 20(21), 5258; https://doi.org/10.3390/ijms20215258 - 23 Oct 2019

Cited by 43 | Viewed by 5875

Abstract

Zn²⁺ deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn²⁺-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn [...] Read more.

Zn²⁺ deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn²⁺-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn²⁺ deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn²⁺ status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn²⁺ uptake in the gut using different nutritional supplementation of Zn²⁺ could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn²⁺ diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn²⁺ in hemostasis. Storage protein metallothionein maintains or releases Zn²⁺ in the cytoplasm, and the dynamic change of this cytoplasmic Zn²⁺ pool is regulated by the redox status of the cell. An increase of labile Zn²⁺ pool can be toxic for the cells, and therefore cytoplasmic Zn²⁺ levels are tightly regulated by several Zn²⁺ transporters located on the cell surface and also on the intracellular membrane of Zn²⁺ storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn²⁺ is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn²⁺ transport and the physiological role of Zn²⁺ store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn²⁺ to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn²⁺ homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

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10 pages, 288 KiB

Open AccessReview

Effects of Estrogens on Platelets and Megakaryocytes

by Marion Dupuis, Sonia Severin, Emmanuelle Noirrit-Esclassan, Jean-François Arnal, Bernard Payrastre and Marie-Cécile Valéra

Int. J. Mol. Sci. 2019, 20(12), 3111; https://doi.org/10.3390/ijms20123111 - 25 Jun 2019

Cited by 31 | Viewed by 5165

Abstract

In women, oral menopausal hormonal therapy (MHT) is associated with adverse effects including an increased incidence of thromboembolic events, classically attributed to an increase in several liver-derived coagulation factors due to hepatic first pass. While platelets are central players in thrombus constitution, their [...] Read more.

In women, oral menopausal hormonal therapy (MHT) is associated with adverse effects including an increased incidence of thromboembolic events, classically attributed to an increase in several liver-derived coagulation factors due to hepatic first pass. While platelets are central players in thrombus constitution, their implication in women treated with estrogens remains incompletely characterized. Platelets and their medullar progenitors, megakaryocytes, express estrogen receptors (ER) that may explain, at least in part, a sensitivity to hormonal changes. The purpose of this review is to summarize our current knowledge of estrogen actions on platelets and megakaryocytes in mice following in vivo administration and in women using MHT. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

32 pages, 810 KiB

Open AccessReview

Biology and Role of Extracellular Vesicles (EVs) in the Pathogenesis of Thrombosis

by Marta Zarà, Gianni Francesco Guidetti, Marina Camera, Ilaria Canobbio, Patrizia Amadio, Mauro Torti, Elena Tremoli and Silvia Stella Barbieri

Int. J. Mol. Sci. 2019, 20(11), 2840; https://doi.org/10.3390/ijms20112840 - 11 Jun 2019

Cited by 118 | Viewed by 7664

Abstract

Extracellular vesicles (EVs) are well-established mediators of cell-to-cell communication. EVs can be released by every cell type and they can be classified into three major groups according to their biogenesis, dimension, density, and predominant protein markers: exosomes, microvesicles, and apoptotic bodies. During their [...] Read more.

Extracellular vesicles (EVs) are well-established mediators of cell-to-cell communication. EVs can be released by every cell type and they can be classified into three major groups according to their biogenesis, dimension, density, and predominant protein markers: exosomes, microvesicles, and apoptotic bodies. During their formation, EVs associate with specific cargo from their parental cell that can include RNAs, free fatty acids, surface receptors, and proteins. The biological function of EVs is to maintain cellular and tissue homeostasis by transferring critical biological cargos to distal or neighboring recipient cells. On the other hand, their role in intercellular communication may also contribute to the pathogenesis of several diseases, including thrombosis. More recently, their physiological and biochemical properties have suggested their use as a therapeutic tool in tissue regeneration as well as a novel option for drug delivery. In this review, we will summarize the impact of EVs released from blood and vascular cells in arterial and venous thrombosis, describing the mechanisms by which EVs affect thrombosis and their potential clinical applications. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

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24 pages, 1229 KiB

Open AccessReview

Thrombosis Risk Associated with Head and Neck Cancer: A Review

by Pierre Haen, Diane Mege, Lydie Crescence, Françoise Dignat-George, Christophe Dubois and Laurence Panicot-Dubois

Int. J. Mol. Sci. 2019, 20(11), 2838; https://doi.org/10.3390/ijms20112838 - 11 Jun 2019

Cited by 25 | Viewed by 5153

Abstract

Venous thromboembolism (VTE) is a common complication for cancer patients. VTE-associated risk varies according to the type of tumor disease. Head and neck cancer is a common cancer worldwide, and most tumors are squamous cell carcinomas due to tobacco and alcohol abuse. The [...] Read more.

Venous thromboembolism (VTE) is a common complication for cancer patients. VTE-associated risk varies according to the type of tumor disease. Head and neck cancer is a common cancer worldwide, and most tumors are squamous cell carcinomas due to tobacco and alcohol abuse. The risk of VTE associated with head and neck (H&N) cancer is considered empirically low, but despite the high incidence of H&N cancer, few data are available on this cancer; thus, it is difficult to state the risk of VTE. Our review aims to clarify this situation and tries to assess the real VTE risk associated with H&N cancer. We report that most clinical studies have concluded that there is a very low thrombosis risk associated with H&N cancer. Even with the biases that often exist, this clinical review seems to confirm that the risk of VTE was empirically hypothesized. Furthermore, we highlight that H&N cancer has all the biological features of a cancer associated with a high thrombosis risk, including a strong expression of procoagulant proteins, modified thrombosis/fibrinolysis mechanisms, and secretions of procoagulant microparticles and procoagulant cytokines. Thus, this is a paradoxical situation, and some undiscovered mechanisms that could explain this clinical biological ambivalence might exist. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

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