Differentiating haemostasis from thrombosis for therapeutic benefit

2013 ◽  
Vol 110 (11) ◽  
pp. 859-867 ◽  
Author(s):  
James D. McFadyen ◽  
Shaun P. Jackson
Keyword(s):  
Arterial Thrombosis ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Bleeding Risk ◽  
Therapeutic Benefit ◽  
Therapeutic Approaches ◽  
Molecular Events ◽  
Heterogeneous Nature ◽  
Flow Changes

SummaryThe central role of platelets in the formation of the primary haemostatic plug as well as in the development of arterial thrombosis is well defined. In general, the molecular events underpinning these processes are broadly similar. Whilst it has long been known that disturbances in blood flow, changes in platelet reactivity and enhanced coagulation reactions facilitate pathological thrombus formation, the precise details underlying these events remain incompletely understood. Intravital microscopy studies have highlighted the dynamic and heterogeneous nature of thrombus development and demonstrated that there are considerable spatiotemporal differences in the activation states of platelets within a forming thrombus. In this review we will consider the factors regulating the activation state of platelets in a developing thrombus and discuss how specific prothrombotic factors may influence this process, leading to excessive thrombus propagation. We will also discuss some potentially novel therapeutic approaches that may reduce excess thrombus development whilst minimising bleeding risk.

scholarly journals Ankhd1 enhances polycystic kidney disease development via promoting proliferation and fibrosis

2020 ◽  
Author(s):  
Foteini Patera ◽  
Guillaume M Hautbergue ◽  
Patricia Wilson ◽  
Paul C Evans ◽  
Albert CM Ong ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Therapeutic Benefit ◽  
Polycystic Kidney ◽  
Molecular Events ◽  
Proliferative Growth ◽  
Kh Domain ◽  
Autosomal Dominant Polycystic Kidney

ABSTRACTAutosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disorder resulting in 10% of patients with renal failure. The molecular events responsible for the relentless growth of cysts are not defined. Thus, identification of novel drivers of ADPKD may lead to new therapies. Ankyrin Repeat and Single KH domain-1 (ANKHD1) controls cancer cell proliferation, yet its role in ADPKD is unexplored. Here, we present the first data that identify ANKHD1 as a driver of proliferative growth in cellular and mouse models of ADPKD. Using the first Ankhd1-deficient mice, we demonstrate that Ankhd1 heterozygosity potently reduces cystic growth and fibrosis, in a genetically orthologous mouse model of ADPKD. We performed transcriptome-wide profiling of patient-derived ADPKD cells with and without ANKHD1 siRNA silencing, revealing a major role for ANKHD1 in the control of cell proliferation and matrix remodelling. We validated the role of ANKHD1 in enhancing proliferation in patient-derived cells. Mechanistically ANKHD1 promotes STAT5 signalling in ADPKD mice. Hence, ANKHD1 is a novel driver of ADPKD, and its inhibition may be of therapeutic benefit.

scholarly journals Functional Genomics for the Identification of Modulators of Platelet-Dependent Thrombus Formation

TH Open ◽  
2018 ◽  
Vol 02 (03) ◽  
pp. e272-e279
Author(s):  
Elien Vermeersch ◽  
Benedicte Nuyttens ◽  
Claudia Tersteeg ◽  
Katleen Broos ◽  
Simon De Meyer ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Cell Types ◽  
Correlative Analysis ◽  
Genome Expression ◽  
Genome Wide ◽  
Whole Genome Expression

AbstractDespite the absence of the genome in platelets, transcription profiling provides important insights into platelet function and can help clarify abnormalities in platelet disorders. The Bloodomics Consortium performed whole-genome expression analysis comparing in vitro–differentiated megakaryocytes (MKs) with in vitro–differentiated erythroblasts and different blood cell types. This allowed the identification of genes with upregulated expression in MKs compared with all other cell lineages, among the receptors BAMBI, LRRC32, ESAM, and DCBLD2. In a later correlative analysis of genome-wide platelet RNA expression with interindividual human platelet reactivity, LLRFIP and COMMD7 were additionally identified. A functional genomics approach using morpholino-based silencing in zebrafish identified various roles for all of these selected genes in thrombus formation. In this review, we summarize the role of the six identified genes in zebrafish and discuss how they correlate with subsequently performed mouse experiments.

scholarly journals Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

2019 ◽  
Vol 20 (22) ◽  
pp. 5707 ◽  
Author(s):  
Angelo Giuseppe Condorelli ◽  
Elena Dellambra ◽  
Elena Logli ◽  
Giovanna Zambruno ◽  
Daniele Castiglia
Keyword(s):  
Squamous Cell ◽  
Epidermolysis Bullosa ◽  
Genetic Determinants ◽  
Therapeutic Approaches ◽  
Molecular Events ◽  
Genes Encoding ◽  
Skin Fragility ◽  
Serious Disease ◽  
Almost All

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, fibrosis and inflammation at lesional skin. These features expose patients to serious disease complications, including the development of cutaneous squamous cell carcinomas (SCCs). Almost all subjects affected with the severe recessive dystrophic EB (RDEB) subtype suffer from early and extremely aggressive SCCs (RDEB-SCC), which represent the first cause of death in these patients. The genetic determinants of RDEB-SCC do not exhaustively explain its unique behavior as compared to low-risk, ultraviolet-induced SCCs in the general population. On the other hand, a growing body of evidence points to the key role of tumor microenvironment in initiation, progression and spreading of RDEB-SCC, as well as of other, less-investigated, EB-related SCCs (EB-SCCs). Here, we discuss the recent advances in understanding the complex series of molecular events (i.e., fibrotic, inflammatory, and immune processes) contributing to SCC development in EB patients, cross-compare tumor features in the different EB subtypes and report the most promising therapeutic approaches to counteract or delay EB-SCCs.

Mechanisms of platelet activation: Need for new strategies to protect against platelet-mediated atherothrombosis

2009 ◽  
Vol 102 (08) ◽  
pp. 248-257 ◽  
Author(s):  
Lisa Jennings
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Antiplatelet Agents ◽  
Bleeding Risk ◽  
Adenosine Diphosphate ◽  
Adp Receptor ◽  
Activation Pathways ◽  
New Strategies

SummaryPlatelets are central mediators of haemostasis at sites of vascular injury, but they also mediate pathologic thrombosis. Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. They also interact with endothelial cells and leukocytes to promote inflammation, which contributes to atherosclerosis. Multiple pathways contribute to platelet activation, and current oral antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor antagonist target the thromboxane A2 and ADP pathways, respectively. Both can diminish activation by other factors, but the extent of their effects depends upon the agonist, agonist strength, and platelet reactivity status. Although these agents have demonstrated significant clinical benefit, residual morbidity and mortality remain high. Neither agent is effective in inhibiting thrombin, the most potent platelet activator. This lack of comprehensive inhibition of platelet function allows continued thrombus formation and exposes patients to risk for recurrent thrombotic events. Moreover, bleeding risk is a substantial limitation of antiplatelet therapy, because these agents target platelet activation pathways critical for both protective haemostasis and pathologic thrombosis. Novel antiplatelet therapies that provide more complete inhibition of platelet activation without increasing bleeding risk could considerably decrease residual risk for ischemic events. Inhibition of the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin is a novel, emerging approach to achieve more comprehensive inhibition of platelet activation when used in combination with current oral antiplatelet agents. PAR-1 inhibition is not expected to increase bleeding risk, as this pathway does not interfere with haemostasis.

A Comprehensive Study of miRNAs in Parkinson’s Disease: Diagnostics and Therapeutic Approaches

2022 ◽  
Vol 21 ◽  
Author(s):  
Saima Owais ◽  
Yasir Hasan Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Therapeutic Approaches ◽  
Molecular Events ◽  
Disease Diagnostics ◽  
Therapeutic Molecules ◽  
Comprehensive Study

Abstract: Parkinson’s disease (PD) is the second most debilitating neurodegenerative movement disorder. It is characterized by the presence of fibrillar alpha-synuclein amassed in the neurons, known as Lewy bodies. Certain cellular and molecular events are involved leading to the degeneration of dopaminergic neurons. However, the origin and implication of such events are still uncertain. Nevertheless, the role of microRNAs (miRNAs) as important biomarkers and therapeutic molecules is unquestionable. The most challenging task by far in PD treatment has been its late diagnosis followed by therapeutics. miRNAs are an emerging hope to meet the need of early diagnosis, thereby promising an improved movement symptom and prolonged life of the patients. The continuous efforts in discovering the role of miRNAs could be made possible by the utilisation of various animal models of PD. These models help us to understand insights into the mechanism of the disease. Moreover, miRNAs have been surfaced as therapeutically important molecules with distinct delivery systems enhancing their success rate. This review aims at providing an outline of different miRNAs implicated in either PD-associated gene regulation or involved in therapeutics.

scholarly journals Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1

2020 ◽  
Vol 126 (4) ◽  
pp. 486-500 ◽  
Author(s):  
Tobias Petzold ◽  
Manuela Thienel ◽  
Lisa Dannenberg ◽  
Philipp Mourikis ◽  
Carolin Helten ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Platelet Activation ◽  
Arterial Thrombosis ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Vitamin K Antagonists ◽  
Factor Xa ◽  
Antiplatelet Effect ◽  
Protease Activated Receptor 1

Rationale: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. Objective: In this study, we hypothesized that rivaroxaban’s antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. Methods and Results: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban’s antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban’s anticoagulatory capacity. Conclusions: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Inhibition of coronary thrombosis and local inflammation by a noncarbohydrate selectin inhibitor

2000 ◽  
Vol 279 (6) ◽  
pp. H3065-H3075 ◽  
Author(s):  
Pierre Zoldhelyi ◽  
Pamela J. Beck ◽  
Robert J. Bjercke ◽  
Judy C. Ober ◽  
X. Hu ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Coronary Thrombosis ◽  
Antithrombotic Effect ◽  
Small Molecular Weight ◽  
Cyclic Flow ◽  
Blocking Antibodies ◽  
Selectin Binding

We tested the hypothesis that selectin inhibition with blocking antibodies or a small-molecular-weight inhibitor of L-, P-, and E-selectin, methoxybenzoylpropionic acid (MBPA), prevents thrombus formation in a canine coronary Folts' model. Cyclic flow variations (CFVs) were induced by crush injury and constriction of the left anterior descending coronary artery in dogs. Systemic infusion of antibodies to P- and L-selectin abolished CFVs, respectively, in 50% and 17% of treated dogs [ P = not significant (NS)]. The combination of P- and L-selectin antibodies suppressed CFVs in 60% of treated dogs ( P = NS). In contrast, systemic selectin blockade by intravenous infusion or local adventitial application of MBPA markedly reduced CFVs and, in addition, reduced myocardial myeloperoxidase (MPO) activity. We conclude that inhibition of L-, P-, and E-selectin binding by a small-molecular-weight, noncarbohydrate compound markedly reduces arterial thrombosis, whereas systemic administration of antibodies to L- and P-selectin fail to reproduce this antithrombotic effect. These results underscore the role of selectins in the pathogenesis of arterial thrombosis under high shear stress and suggest that inhibition of P- and L- selectin may not suffice to prevent thrombus formation in this model. The role of E-selectin in thrombus formation in this model awaits further testing.

Platelet — vessel wall interaction: role of blood clotting

1981 ◽  
Vol 294 (1072) ◽  
pp. 355-371 ◽  
Keyword(s):  
Arterial Thrombosis ◽  
Vessel Wall ◽  
Vascular Tissue ◽  
Thrombus Formation ◽  
Blood Platelets ◽  
Factor X ◽  
Physiological Relevance ◽  
Arterial Thrombus ◽  
Wall Interaction

Vascular damage initiates not only the adhesion and aggregation of blood platelets but also coagulation, which is of mixed (intrinsic and extrinsic) origin. Evidence is presented that thrombin, generated as a result of the injury, is a prerequisite for platelet aggregation. Platelets, after activation, in their turn promote coagulation. Prostaglandin I 2 (PGI 2 or prostacyclin) inhibits coagulation induced by damaged vascular tissue. This effect of PGI 2 is mediated by the inhibition of platelets in their participation in the generation of factor X a and thrombin. Dietary cod liver oil, by changing plasma coagulability, decreases the procoagulation activity of vessel walls, and arterial thrombosis. Another fish oil with similar effects on plasma coagulability and some other haemostatic parameters does not modify vessel wall-induced clotting, nor does it significantly lower arterial thrombosis tendency; this indicates the physiological relevance of vessel wall-induced clotting in arterial thrombus formation. Some evidence is also given for the importance of vessel wall-induced clotting in primary haemostasis.

The Actin Regulator Coronin-1A Modulates Platelet Shape Change and Consolidates Arterial Thrombosis

2018 ◽  
Vol 118 (12) ◽  
pp. 2098-2111 ◽  
Author(s):  
Thomas Stocker ◽  
Joachim Pircher ◽  
Artid Skenderi ◽  
Andreas Ehrlich ◽  
Clemens Eberle ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Actin Polymerization ◽  
Thrombus Formation ◽  
Shape Change ◽  
Actin Binding ◽  
Cellular Processes ◽  
Reduced Density ◽  
Induced Aggregation ◽  
Platelet Shape

AbstractCoronin-1A (Coro1A) belongs to a family of highly conserved actin-binding proteins that regulate cytoskeletal re-arrangement. In mammalians, Coro1A expression is most abundant in the haematopoietic lineage, where it regulates various cellular processes. The role of Coro1A in platelets has been previously unknown. Here, we identified Coro1A in human and mouse platelets. Genetic absence of Coro1A in mouse platelets inhibited agonist-induced actin polymerization and altered cofilin phosphoregulation, leading to a reduction in spreading and low-dose collagen induced aggregation. Furthermore, Coro1A-deficient mice displayed a defect in ferric chloride-induced arterial thrombosis with prolonged thrombus formation and reduced thrombus size. Immunofluorescence analysis revealed a less compact thrombus structure with reduced density of platelets and fibrinogen. In summary, Coro1A has a role in platelet biology with impact on spreading, aggregation and thrombosis.

BF061, a novel antiplatelet and antithrombotic agent targeting P2Y12 receptor and phosphodiesterase

2011 ◽  
Vol 106 (12) ◽  
pp. 1203-1214 ◽  
Author(s):  
Liang Hu ◽  
Zhichao Fan ◽  
Hongguang Du ◽  
Ran Ni ◽  
Si Zhang ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Antiplatelet Agent ◽  
Atp Release ◽  
Bleeding Risk ◽  
P2y12 Receptor ◽  
Antithrombotic Agent ◽  
Thrombosis Model ◽  
P2y12 Antagonists ◽  
Pde Inhibition

SummaryThe addition of phosphodiesterase (PDE) inhibitors has been reported to potentiate the antithrombotic effects of P2Y12 antagonists without increasing bleeding risk. In this study, we report that a potent antiplatelet agent, 2-ethylthio-6-phenethylaminoadenosine (BF061), inhibits platelet activation and thrombosis via P2Y12 antagonism and PDE inhibition. We explored the antiplatelet mechanism of BF061 by measuring cAMP, cGMP levels, PDE activity, and the interaction between ADP and P2Y12 using atomic force microscopy. The antithrombotic effect of BF061 was evaluated in mice using intravital microscopy in FeCl3-induced mesenteric and laser-induced cremasteric arterial thrombosis models. BF061 robustly inhibited platelet aggregation and ATP release induced by multiple platelet agonists via P2Y12 antagonism and PDE inhibition. Interestingly, despite being structurally similar to BF061, P2Y12 receptor antagonist AR-C69931MX had no effect on human platelet PDE. In FeCl3-induced mesenteric arterial thrombosis model, BF061 effectively prevented thrombus formation similarly to clopidogrel; it also reduced thrombus volume in laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at an antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y12 and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.

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