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Circulation Dec 2021LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association...
BACKGROUND
LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that ) reduces LNK function and that LNK-deficient mice display prominent platelet-neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet-neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic deficiency.
METHODS
We bred mice with combined deficiency of and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2).
RESULTS
-deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated platelets promoted increased NETosis when incubated with neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from platelets, as well as increased priming and response of neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in mice. We also showed increased NETosis when human induced pluripotent stem cell-derived ) neutrophils were incubated with ) platelet/megakaryocytes, but not in isogenic ) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2 mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic and clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with controls.
CONCLUSIONS
Hematopoietic deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.
Topics: Adaptor Proteins, Signal Transducing; Animals; Arteries; Blood Platelets; Mice; Mice, Knockout; Neutrophils; Oxidation-Reduction; Phospholipids; Platelet Aggregation; Thrombosis
PubMed: 34846914
DOI: 10.1161/CIRCULATIONAHA.121.056414 -
Mayo Clinic Proceedings Feb 2021
Topics: Arteries; COVID-19; Humans; Thrombosis
PubMed: 33549245
DOI: 10.1016/j.mayocp.2020.12.009 -
Circulation Research Apr 2020Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by... (Review)
Review
Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood with the intimal surface of diseased arteries and propagate and amplify the regional injury. NETs thus furnish a previously unsuspected link between inflammation, innate immunity, thrombosis, oxidative stress, and cardiovascular diseases. In response to disease-relevant stimuli, neutrophils undergo a specialized series of reactions that culminate in NET formation. DNA derived from either nuclei or mitochondria can contribute to NET formation. The DNA liberated from neutrophils forms a reticular mesh that resembles morphologically a net, rendering the acronym NETs particularly appropriate. The DNA backbone of NETs not only presents intrinsic neutrophil proteins (eg, MPO [myeloperoxidase] and various proteinases) but can gather other proteins found in blood (eg, tissue factor procoagulant). This review presents current concepts of neutrophil biology, the triggers to and mechanisms of NET formation, and the contribution of NETs to atherosclerosis and to thrombosis. We consider the use of markers of NETs in clinical studies. We aim here to integrate critically the experimental literature with the growing body of clinical information regarding NETs.
Topics: Animals; Arteries; Atherosclerosis; Biomarkers; Blood Coagulation; Extracellular Traps; Humans; Inflammation; Inflammation Mediators; Neutrophils; Plaque, Atherosclerotic; Reactive Oxygen Species; Rupture, Spontaneous; Signal Transduction; Thrombosis
PubMed: 32324499
DOI: 10.1161/CIRCRESAHA.120.315931 -
Arteriosclerosis, Thrombosis, and... Sep 2020Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different... (Review)
Review
Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different vascular territories. Acute coronary syndrome is a relatively common manifestation of coronary atherosclerotic disease, wherein the thrombosis occurs secondary to disruption (65%-75%) and erosion (25%-35%) of the fibrous caps of atheromatous plaques. The plaques associated with plaque rupture have large necrotic cores and thin and inflamed fibrous caps. However, the pathological manifestations of peripheral artery disease result from thrombosis regardless of the extent of atherosclerosis. Approximately 75% of peripheral arteries with significant stenosis demonstrate presence of thrombi, of which two-thirds have thrombi associated with insignificant atherosclerosis. The presence of obliterative thrombi in peripheral arteries of patients with critical limb ischemia in the absence of coronary artery-like lesions suggests a locally thrombogenic or remotely embolic basis of disease. Extensive calcification of the medial vascular layer is commonly observed. In this review, we have described and compared the pathological basis of coronary and peripheral artery disease in patients with acute coronary syndrome and critical limb ischemia. It is expected that pathogenetic characterization would allow for definition of strategic targets for superior management of peripheral artery disease.
Topics: Acute Coronary Syndrome; Arteries; Coronary Artery Disease; Coronary Vessels; Critical Illness; Disease Progression; Fibrinolytic Agents; Fibrosis; Humans; Ischemia; Peripheral Arterial Disease; Plaque, Atherosclerotic; Prognosis; Rupture, Spontaneous; Thrombosis
PubMed: 32673526
DOI: 10.1161/ATVBAHA.119.312864 -
British Journal of Pharmacology Nov 2021Thrombosis contributes to one in four deaths worldwide and is the cause of a large proportion of mortality and morbidity. A reliable and rapid diagnosis of thrombosis... (Review)
Review
Thrombosis contributes to one in four deaths worldwide and is the cause of a large proportion of mortality and morbidity. A reliable and rapid diagnosis of thrombosis will allow for immediate therapy, thereby providing significant benefits to patients. Molecular imaging is a fast-growing and captivating area of research, in both preclinical and clinical applications. Major advances have been achieved by improvements in three central areas of molecular imaging: - (1) better markers for diseases, with increased sensitivity and selectivity, (2) optimised contrast agents with improved signal to noise ratio and (3), progress in scanner technologies with higher sensitivity and resolution. Clinically available imaging modalities used for molecular imaging include magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound, as well as nuclear imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). In the preclinical imaging field, optical (fluorescence and bioluminescent) molecular imaging has provided new mechanistic insights in the pathology of thromboembolic diseases. Overall, the advances in molecular imaging, driven by the collaboration of various scientific disciplines, have substantially contributed to an improved understanding of thrombotic disease and raise the exciting prospect of earlier diagnosis and individualised therapy for cardiovascular diseases. As such, these advances hold significant promise to be translated to clinical practice and ultimately to reduce mortality and morbidity in patients with thromboembolic diseases. LINKED ARTICLES: This article is part of a themed issue on Molecular imaging - visual themed issue. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.21/issuetoc.
Topics: Arteries; Biomarkers; Humans; Molecular Imaging; Thrombosis; Venous Thrombosis
PubMed: 34296431
DOI: 10.1111/bph.15635 -
JACC. Cardiovascular Interventions May 2021
Topics: Femoral Artery; Humans; Stents; Thrombosis; Treatment Outcome
PubMed: 34016413
DOI: 10.1016/j.jcin.2021.04.023 -
Current Problems in Cardiology Oct 2022For more than 2 years, health care systems have been floundering in a massive crisis of coronavirus disease 2019 (COVID-19) pandemic. While acute respiratory distress... (Review)
Review
For more than 2 years, health care systems have been floundering in a massive crisis of coronavirus disease 2019 (COVID-19) pandemic. While acute respiratory distress syndrome is the main complication in patients with COVID-19, as the pandemic continues, more data about the nonrespiratory effects of the coronavirus is obtained, including developing Coagulopathy-related manifestations, in the form of venous and arterial thromboembolism. Although arterial thrombosis a rare complication of this disease, it proves to be an effective factor in the mortality and morbidity of COVID-19 patients. The pathophysiology of thrombosis reveals a complex relation between hemostasis and immune system that can be disrupted by COVID-19. Thrombectomy, anticoagulant therapy, and thrombolysis are the main treatments in these patients. In addition, appropriate thromboprophylaxis treatment should be considered in COVID-19 patients. In this article, we have successfully reviewed the arterial thrombotic events in patients reported around the world, including the diagnostic and management method of choice.
Topics: Anticoagulants; Arteries; COVID-19; Humans; SARS-CoV-2; Thrombosis; Venous Thromboembolism
PubMed: 34571103
DOI: 10.1016/j.cpcardiol.2021.100992 -
Journal of Thrombosis and Haemostasis :... Jun 2013Microparticles (MPs) represent a heterogeneous population of submicronic vesicles that are released in response to cell activation or apoptosis. MPs harbor a large... (Review)
Review
Microparticles (MPs) represent a heterogeneous population of submicronic vesicles that are released in response to cell activation or apoptosis. MPs harbor a large repertoire of cell surface receptors and mRNA and biological activities representative of their parent cells and related to their involvement in many biological functions. Although MP generation is a physiological response, a dramatic increase in circulating MPs is detectable in a variety of thrombosis-associated disorders compared with healthy individuals. In this review, we will discuss a new vision of MPs as complex and ambivalent structures that express both activators and inhibitors of coagulation but also convey fibrinolytic properties. After summarizing our current knowledge about the role of MPs in venous and arterial thrombosis, this review will explore how this new vision of MPs influences their definition as emergent biomarkers in thrombotic diseases. Among the studies that have aimed to establish a link between thrombosis and MPs, a few studies have demonstrated a predictive value of MPs. So far, it is unclear whether this limited causative association is the result of current technical concerns and limited standardization or has to be integrated into a more complex vision of the role of MPs as key systems for regulating the balance between coagulation and fibrinolysis.
Topics: Animals; Arteries; Fibrinolysis; Humans; Microspheres; Thrombosis; Veins
PubMed: 23809108
DOI: 10.1111/jth.12268 -
PloS One 2021The present meta-analysis aimed to investigate the differences in the incidence of thrombosis and vascular compromise in arterial anastomosis between microvascular... (Meta-Analysis)
Meta-Analysis
The present meta-analysis aimed to investigate the differences in the incidence of thrombosis and vascular compromise in arterial anastomosis between microvascular anastomotic devices and hand-sewn techniques during free tissue transfer in the head and neck. We searched for articles in PubMed/Medline, CNKI, WANFANG DATA, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science, from January 1, 1962 till April 1, 2020 that reported data of microvascular anastomosis during free tissue transfer in the head and neck. The incidence of arterial thrombosis or vascular compromise, or both was the primary outcome. The secondary outcome was anastomotic time. We also assessed the sensitivity and the risk of bias. This meta-analysis included 583 arterial anastomoses from six studies. The group using microvascular anastomotic devices tended to have an increased incidence of arterial thrombosis and vascular compromise (risk ratio (RR), 3.42; P = 0.38; 95% confidence interval (CI), 0.91-12.77). The hand-sewn technique took significantly longer to perform the anastomosis compared with that of the microvascular anastomotic devices (weighted mean difference, 15.26 min; P<0.01; 95% CI, 14.65-15.87). Microvascular anastomotic devices might increase the risk of arterial thrombosis and vascular compromise compared with the hand-sewn technique; however, further randomized controlled trials are needed to provide a more accurate estimate. The application of microvascular anastomotic devices will help to reduce anastomotic surgery time and achieve acceptable vessel opening, benefiting from the developments of arterial couplers and microsurgical techniques.
Topics: Anastomosis, Surgical; Arteries; Databases, Factual; Free Tissue Flaps; Head; Humans; Neck; Risk; Thrombosis; Vascular Diseases
PubMed: 33793654
DOI: 10.1371/journal.pone.0249418 -
The Netherlands Journal of Medicine Jan 2011
Topics: Arteries; Humans; Risk Factors; Thrombosis; Venous Thrombosis
PubMed: 21325694
DOI: No ID Found