scholarly journals Platelet GPVI (Glycoprotein VI) and Thrombotic Complications in the Venous System

2021 ◽  
Author(s):  
Gina Perrella ◽  
Magdolna Nagy ◽  
Steve P. Watson ◽  
Johan W.M. Heemskerk
Keyword(s):  
Venous Thromboembolism ◽  
Cancer Metastasis ◽  
Pulmonary Thromboembolism ◽  
Thrombus Formation ◽  
Current Evidence ◽  
Immunoglobulin Receptor ◽  
Venous Thrombus ◽  
Glycoprotein Vi ◽  
Ligand Interactions ◽  
Thrombotic Complications

The immunoglobulin receptor GPVI (glycoprotein VI) is selectively expressed on megakaryocytes and platelets and is currently recognized as a receptor for not only collagen but also a variety of plasma and vascular proteins, including fibrin, fibrinogen, laminin, fibronectin, and galectin-3. Deficiency of GPVI is protective in mouse models of experimental thrombosis, pulmonary thromboembolism as well as in thromboinflammation, suggesting a role of GPVI in arterial and venous thrombus formation. In humans, platelet GPVI deficiency is associated with a mild bleeding phenotype, whereas a common variant rs1613662 in the GP6 gene is considered a risk factor for venous thromboembolism. However, preclinical studies on the inhibition of GPVI-ligand interactions are focused on arterial thrombotic complications. In this review we discuss the emerging evidence for GPVI in venous thrombus formation and leukocyte-dependent thromboinflammation, extending to venous thromboembolism, pulmonary thromboembolism, and cancer metastasis. We also recapitulate indications for circulating soluble GPVI as a biomarker of thrombosis-related complications. Collectively, we conclude that the current evidence suggests that platelet GPVI is also a suitable cotarget in the prevention of venous thrombosis due to its role in thrombus consolidation and platelet-leukocyte complex formation.

Re-modelling of venous thrombosis

2013 ◽  
Vol 28 (1_suppl) ◽  
pp. 25-28 ◽  
Author(s):  
R D Malgor ◽  
N Labropoulos
Keyword(s):  
Venous Thromboembolism ◽  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Temporal Relation ◽  
Morbidity And Mortality ◽  
Basic Knowledge ◽  
Venous Thrombus ◽  
Prompt Treatment ◽  
Common Causes

Venous thromboembolism is one of the most common causes of morbidity and mortality in modern societies. The entirety of events involved in venous thrombus formation and resolution remains to be elucidated. Temporal relation between the initial cellular insult, thrombus formation and resolution is critical for instituting a prompt treatment. This paper analyses the current basic knowledge and the events involved in venous remodelling after an episode of venous thrombosis.

scholarly journals Urokinase Attenuates Pulmonary Thromboembolism in an Animal Model by Inhibition of Inflammatory Response

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Ying Shi ◽  
Zhirong Zhang ◽  
Danli Cai ◽  
Jing Kuang ◽  
Shuifang Jin ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Animal Model ◽  
Inflammatory Response ◽  
Inflammatory Cell ◽  
Pulmonary Thromboembolism ◽  
Thrombus Formation ◽  
Inflammatory Cells ◽  
Hemodynamic Instability ◽  
Synergistic Action ◽  
Determining Factor

Inflammatory response is an important determining factor for the mortality of patients with pulmonary thromboembolism. Inflammatory mediators can promote thrombus formation and increase hemodynamic instability. Urokinase is a commonly used drug for the treatment of PTE. The effect of urokinase on inflammatory reaction in PTE is still unclear. Our study was aimed at evaluating the effects of the intervention of urokinase and urokinase combined with aspirin in PTE rats. Results revealed that a large amount of infiltrated inflammatory cells surrounding the bronchus, vessels, and pulmonary mesenchyme, and even pulmonary abscess were observed in the PTE rats. CX3CL1/CX3CR1 coexpression, CX3CL1/NF-κB coexpression, and TXA2 were significantly higher. After treatment with urokinase, pulmonary embolism was partially dissolved and inflammatory cell infiltration was significantly reduced. The expression of TNNI3, BNP, D2D, PASP, PADP, PAMP, and TXA2, as well as CX3CL1/CX3CR1 coexpression and CX3CL1/NF-κB coexpression were significantly lowered. Aspirin showed no synergistic action. Therefore, these findings suggested the occurrence of inflammation during the process of PTE in rats. Urokinase treatment reduced the inflammatory response.

scholarly journals Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets

2017 ◽  
Vol 37 (5) ◽  
pp. 823-835 ◽  
Author(s):  
Christopher W. Smith ◽  
Steven G. Thomas ◽  
Zaher Raslan ◽  
Pushpa Patel ◽  
Maxwell Byrne ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Thrombus Formation ◽  
Physiological Role ◽  
Src Family Kinase ◽  
Glycoprotein Vi ◽  
Collagen Receptor ◽  
Deficient Mice

Objective— Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif–containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif–containing collagen receptor complex, glycoprotein VI-FcRγ-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored. In this study, we investigate the role of LAIR-1 in megakaryocyte development and platelet production by generating LAIR-1–deficient mice. Approach and Results— Mice lacking LAIR-1 exhibit a significant increase in platelet counts, a prolonged platelet half-life in vivo, and increased proplatelet formation in vitro. Interestingly, platelets from LAIR-1–deficient mice exhibit an enhanced reactivity to collagen and the glycoprotein VI–specific agonist collagen-related peptide despite not expressing LAIR-1, and mice showed enhanced thrombus formation in the carotid artery after ferric chloride injury. Targeted deletion of LAIR-1 in mice results in an increase in signaling downstream of the glycoprotein VI–FcRγ-chain and integrin αIIbβ3 in megakaryocytes because of enhanced Src family kinase activity. Conclusions— Findings from this study demonstrate that ablation of LAIR-1 in megakaryocytes leads to increased Src family kinase activity and downstream signaling in response to collagen that is transmitted to platelets, rendering them hyper-reactive specifically to agonists that signal through Syk tyrosine kinases, but not to G-protein–coupled receptors.

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin

2021 ◽  
Author(s):  
Delia I. Fernández ◽  
Alicia Veninga ◽  
Bibian M. E. Tullemans ◽  
Constance C. F. M. J. Baaten ◽  
Linsey J. F. Peters ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Patients ◽  
Kinase Inhibitor ◽  
Synergistic Effects ◽  
Thrombus Formation ◽  
Type I ◽  
Glycoprotein Vi ◽  
Fibrin Formation ◽  
Increased Risk

Abstract Background Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation. Methods Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca2+]i, aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed. Results Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca2+ elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation. Conclusion Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.

Thromboinflammation as a Driver of Venous Thromboembolism

2021 ◽  
Vol 41 (06) ◽  
pp. 428-432
Author(s):  
Nadine Gauchel ◽  
Krystin Krauel ◽  
Muataz Ali Hamad ◽  
Christoph Bode ◽  
Daniel Duerschmied
Keyword(s):  
Innate Immunity ◽  
Venous Thromboembolism ◽  
Host Defense ◽  
Thrombus Formation ◽  
Pathological Process ◽  
Defense Systems ◽  
Underlying Mechanisms

AbstractThrombus formation has been identified as an integral part in innate immunity, termed immunothrombosis. Activation of host defense systems is known to result in a procoagulant environment. In this system, cellular players as well as soluble mediators interact with each other and their dysregulation can lead to the pathological process of thromboinflammation. These mechanisms have been under intensified investigation during the COVID-19 pandemic. In this review, we focus on the underlying mechanisms leading to thromboinflammation as one trigger of venous thromboembolism.

scholarly journals Prevention of venous thromboembolism in hospitalized patients with chronic kidney disease

2013 ◽  
pp. 269-276
Author(s):  
Marcora Mandreoli ◽  
Antonio Santoro
Keyword(s):  
Renal Failure ◽  
Venous Thromboembolism ◽  
Renal Disease ◽  
Case Reports ◽  
Current Evidence ◽  
High Morbidity ◽  
Medical Patients ◽  
Medically Ill ◽  
Increased Risk ◽  
Therapeutic Doses

Despite the high morbidity and mortality associated with venous thromboembolism in hospitalized medical patients with a number of risk factors, and large evidence that prophylaxis is effective, prophylaxis rates remain elusive in medically ill patients. Furthermore, in patients with renal failure, prophylaxis often is omitted or sub-optimal, due to fear of provoking hemorrhage. Patients with end-stage renal disease often have platelet deficits. Low molecular weight heparin (LMWH) therapy may also be difficult to manage in these cases because LMWH clearance is largely dependent on the kidneys. Administration of LMWH to patients with some degree of renal failure may lead to bioaccumulation of anti-Xa activity with an increased risk of bleeding. In recent years, LMWH has largely replaced unfractionated heparin (UFH) for the treatment and prophylaxis of thromboembolic disease. LMWHs have been shown to be superior to UFH in the prevention of venous thromboembolism. They are also easier to administer and do not require laboratory monitoring. However, several case reports and a metaanalysis indicate that the use of LMWHs at therapeutic doses in patients with advanced renal failure can be associated with major bleeding with serious adverse effects. In this paper, we review recent evidence supporting the safety of LMWHs at prophylactic doses in patients with mild or moderate renal disease. Current evidence suggests that bioaccumulation of enoxaparin (the most widely used LMWH) can occur when the drug is used at standard therapeutic doses in patients with severely impaired renal function. This risk can be reduced by empiric dose reduction or monitoring of anti-Xa heparin levels.

Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo

2006 ◽  
Vol 95 (05) ◽  
pp. 763-766 ◽  
Author(s):  
Andreas Bültmann ◽  
Christian Herdeg ◽  
Zhongmin Li ◽  
Götz Münch ◽  
Christine Baumgartner ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Vascular Injury ◽  
Carotid Arteries ◽  
Thrombus Formation ◽  
Critical Role ◽  
Local Delivery ◽  
Computer Assisted ◽  
Glycoprotein Vi ◽  
Collagen Receptor

SummaryPlatelet-mediated thrombus formation at the site of vascular injury isa major trigger for thrombo-ischemic complications after coronary interventions. The platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in the initiation of arterial thrombus formation. Endothelial denudation of the right carotid artery in rabbits was induced through balloon injury. Subsequently, local delivery of soluble, dimeric fusion protein of GPVI (GPVI-Fc) (n=7) or control Fc (n=7) at the site of vascular injury was performed with a modified double-balloon drugdelivery catheter.Thrombus area within the injured carotid artery was quantified using a computer-assisted image analysis and was used as index of thrombus formation.The extent of thrombus formation was significantly reduced in GPVI-Fc- compared with control Fc-treated carotid arteries (relative thrombus area, GPVI-Fc vs. Fc: 9.3 ± 4.2 vs. 2.3 ± 1.7, p<0.001). Local delivery of soluble GPVI resulted in reduced thrombus formation after catheter-induced vascular injury.These data suggest a selective pharmacological modulation of GPVI-collagen interactions to be important for controlling onset and progression of pathological arterial thrombosis, predominantly or even exclusively at sites of injured carotid arteries in the absence of systemic platelet therapy.

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