scholarly journals Predictive modelling of thrombus formation in diabetic retinal microaneurysms

2020 ◽  
Vol 7 (8) ◽  
pp. 201102
Author(s):  
He Li ◽  
Konstantina Sampani ◽  
Xiaoning Zheng ◽  
Dimitrios P. Papageorgiou ◽  
Alireza Yazdani ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Computational Models ◽  
Thrombus Formation ◽  
Imaging Techniques ◽  
Blood Flow Rate ◽  
Predictive Modelling ◽  
Clinical Findings ◽  
Particle Model ◽  
Ophthalmic Imaging ◽  
Retinal Microaneurysms

Microaneurysms (MAs) are one of the earliest clinically visible signs of diabetic retinopathy (DR). Vision can be reduced at any stage of DR by MAs, which may enlarge, rupture and leak fluid into the neural retina. Recent advances in ophthalmic imaging techniques enable reconstruction of the geometries of MAs and quantification of the corresponding haemodynamic metrics, such as shear rate and wall shear stress, but there is lack of computational models that can predict thrombus formation in individual MAs. In this study, we couple a particle model to a continuum model to simulate the platelet aggregation in MAs with different shapes. Our simulation results show that under a physiologically relevant blood flow rate, thrombosis is more pronounced in saccular-shaped MAs than fusiform-shaped MAs, in agreement with recent clinical findings. Our model predictions of the size and shape of the thrombi in MAs are consistent with experimental observations, suggesting that our model is capable of predicting the formation of thrombus for newly detected MAs. This is the first quantitative study of thrombosis in MAs through simulating platelet aggregation, and our results suggest that computational models can be used to predict initiation and development of intraluminal thrombus in MAs as well as provide insights into their role in the pathophysiology of DR.

Inhibition of Arterial Thrombus Formation in Two Canine Models: Comparison of Ancrod, a Fibrinogen-Depleting Agent, the Thrombin-Inhibitor r-Hirudin, and the Glycoprotein IIb/IIIa-Receptor Antagonist Ro 43-8857

1995 ◽  
Vol 74 (05) ◽  
pp. 1353-1360 ◽  
Author(s):  
K Rübsamen ◽  
W Hornberger ◽  
M Kirchengast
Keyword(s):  
Blood Flow ◽  
Platelet Aggregation ◽  
Carotid Artery ◽  
Thrombus Formation ◽  
Blood Flow Rate ◽  
Artery Blood Flow ◽  
Fibrinogen Binding ◽  
Arterial Thrombus ◽  
Canine Models ◽  
Fibrinogen Depleting Agent

SummaryInhibition of arterial thrombus formation by ancrod, a fibrinogen depleting agent isolated from a snake venom, r-hirudin, an inhibitor of thrombin-mediated fibrinogen cleavage, or the glycoprotein (GP)IIb/IIIa-receptor antagonist Ro 43-8857 interfering with fibrinogen binding to platelets, was evaluated in two canine models. As a marker of platelet-dependent thrombus formation, cyclic blood flow reductions (CFR) were induced in the left coronary artery (LAD) of mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. In the second model CFRs were induced by thrombolysis of a copper coil-induced thrombus in the carotid artery. Blood flow rate during the reocclusion phase was used as an additional parameter of efficacy.The frequency of CFRs used as indicator of platelet aggregation and adhesion was significantly diminished by all treatments in both the carotid artery- and the LAD-model. In the LAD-model, following ancrod treatment, CFRs were correlated with plasma fibrinogen concentrations. Carotid artery blood flow after reperfusion, used as indicator of occlusive thrombus formation, rapidly declined to zero in the control group but remained at a high level after treatment with ancrod or r-hirudin. Ro 43-8857 at the selected dose improved blood flow rate only to a minor degree but prolonged the bleeding time from a mean value of 87.2 ± 10.9 s (n = 24) to values >300 s in 50% of the animals.Our results indicate that CFRs as indicator of platelet aggregation and adhesion are inhibited by either treatments. Blood flow as indicator of occlusive thrombus formation, however, is effectively improved by ancrod and r-hirudin only. Inhibition of fibrinogen binding to platelet GPIIb/IIIa receptors alone was found to be a less potent antithrombotic principle in this model.

Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 566-576 ◽  
Author(s):  
Mhairi J. Maxwell ◽  
Erik Westein ◽  
Warwick S. Nesbitt ◽  
Simon Giuliano ◽  
Sacha M. Dopheide ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Imaging Techniques ◽  
Platelet Aggregates ◽  
Adhesive Interactions ◽  
Membrane Tethers ◽  
Atherosclerotic Plaque Rupture

Abstract Disturbances of blood flow at sites of atherosclerotic plaque rupture are one of the key pathogenic events promoting platelet activation and arterial thrombus formation. Shear effects of platelets have been extensively investigated in vitro; however, the mechanisms by which shear promotes platelet aggregation in vivo remain incompletely understood. By employing high-resolution imaging techniques to in vitro and in vivo thrombosis models, we demonstrate a unique mechanism initiating shear-dependent platelet aggregation involving aggregate formation between discoid platelets. These discoid platelet aggregates are initially unstable and result from the development of membrane tethers between coadhering platelets. Tether formation involves the adhesive function of GPIb/V/IX and integrin αIIbβ3, and conversion of discoid platelet aggregates into stable aggregates requires released ADP. The efficiency of this process is regulated by 3 independent variables, including the reactivity of the adhesive substrate, the level of shear flow, and the platelet density at the adhesive surface. These studies identify a new mechanism initiating platelet aggregation that is critically influenced by shear, physical proximity between translocating platelets, and membrane tether formation. Moreover, they provide a model to explain how the discoid morphology of platelets facilitates the maintenance of adhesive interactions with thrombogenic surfaces under high shear stress conditions.

ADP Plays a Key Role in Thrombogenesis in Rats

1988 ◽  
Vol 59 (02) ◽  
pp. 225-230 ◽  
Author(s):  
J P Maffrand ◽  
A Bernat ◽  
D Delebassée ◽  
G Defreyn ◽  
J P Cazenave ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Vascular Wall ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Silk Thread ◽  
Dense Granules ◽  
Prolonged Bleeding Time ◽  
Venous Shunt

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

1994 ◽  
Vol 71 (01) ◽  
pp. 095-102 ◽  
Author(s):  
Désiré Collen ◽  
Hua Rong Lu ◽  
Jean-Marie Stassen ◽  
Ingrid Vreys ◽  
Tsunehiro Yasuda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bolus Injection ◽  
Cell Injury ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Thrombotic Occlusion ◽  
Antithrombotic Effects

SummaryCyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor.The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time.TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.

Antiplatelet Effect of FK633, a Platelet Glycoprotein Ilb/IIIa Antagonist, on Thrombus Formation and Vascular Patency after Thrombolysis in the Injured Hamster Carotid Artery

1997 ◽  
Vol 77 (03) ◽  
pp. 562-567 ◽  
Author(s):  
Takehiro Kaida ◽  
Hiroyuki Matsuno ◽  
Masayuki Niwa ◽  
Osamu Kozawa ◽  
Hideo Miyata ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Vascular Injury ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Separate Experiment ◽  
Platelet Glycoprotein ◽  
Neointima Formation ◽  
Vascular Patency ◽  
Injured Artery

SummaryThe antithrombotic and restenosis-preventing effects of FK633, an inhibitor of platelet aggregation via binding to the glycoprotein (GP) Ilb/IIIa receptor, were studied. IC50 value of FK633 against platelet aggregation ex vivo induced by 2.5 |iM adenosine diphosphate (ADP) was 5.4 X 10"7 M as determined using hamster platelet rich plasma. The inhibitory effect was also investigated in vivo on thrombus formation at the carotid arterial wall injured by a modified catheter. As a control, the left carotid artery was injured and the time required to develop a thrombotic occlusion (3.9 ±1.1 min, mean ± S.E.M., n = 18) was determined. Then, the right carotid artery of the same animal was injured while a continuous intravenous (i.v.) infusion of FK633 was administered at doses of 0 (saline), 0.1,0.3 or 1.0 mg/kg/h. The time to occlusion was dose-dependently prolonged. In a separate experiment, 10% of the total tPA dose (0.52 mg/kg) was injected into the injured artery as a bolus and the remaining was infused i.v. at a constant rate for 30 min. When FK633 (0.3 or 1.0 mg/kg/h) was infused together with tPA, late patency of the reperfused artery was much improved as compared with that of treatment with tPA alone. Bleeding time, measured at the end of the tPA infusion, was markedly prolonged when the higher dose of FK633 (1.0 mg/kg/h) was coadministered, however coadministration of the lower dose of FK633 (0.3 mg/kg/h) was almost without prolongation on the bleeding time, despite a significant effect on the vascular patency after thrombolysis. Next, neointima formation was evaluated 2 weeks after the vascular injury. When FK633 (0.3 mg/kg/h) was continuously infused i. v. by an implanted osmotic pump for 3,7 or 14 days after the vascular injury, the neointimal area formation was significantly suppressed in the treatment groups for 7 or 14 days. These findings suggest that FK633 inhibits platelet activation in the injured artery and improves vascular patency after thrombolysis with tPA with a concomitant suppression of neointima formation.

Modeling fine particles and alkali metal compound behavior in a kraft recovery boiler

TAPPI Journal ◽  
2012 ◽  
Vol 11 (7) ◽  
pp. 9-14 ◽  
Author(s):  
AINO LEPPÄNEN ◽  
ERKKI VÄLIMÄKI ◽  
ANTTI OKSANEN
Keyword(s):  
Alkali Metal ◽  
Computational Models ◽  
Fine Particles ◽  
Black Liquor ◽  
Melting Behavior ◽  
Metal Compound ◽  
Effect Of Temperature ◽  
Particle Model ◽  
Boiler Furnace ◽  
Recovery Boiler

Under certain conditions, ash in black liquor forms a locally corrosive environment in a kraft recovery boiler. The ash also might cause efficiency losses and even boiler shutdown because of plugging of the flue gas passages. The most troublesome compounds in a fuel such as black liquor are potassium and chlorine because they change the melting behavior of the ash. Fouling and corrosion of the kraft recovery boiler have been researched extensively, but few computational models have been developed to deal with the subject. This report describes a computational fluid dynamics-based method for modeling the reactions between alkali metal compounds and for the formation of fine fume particles in a kraft recovery boiler furnace. The modeling method is developed from ANSYS/FLUENT software and its Fine Particle Model extension. We used the method to examine gaseous alkali metal compound and fine fume particle distributions in a kraft recovery boiler furnace. The effect of temperature and the boiler design on these variables, for example, can be predicted with the model. We also present some preliminary results obtained with the model. When the model is developed further, it can be extended to the superheater area of the kraft recovery boiler. This will give new insight into the variables that increase or decrease fouling and corrosion

scholarly journals Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 933
Author(s):  
Fien Demeulemeester ◽  
Karin de Punder ◽  
Marloes van Heijningen ◽  
Femke van Doesburg
Keyword(s):  
Risk Factor ◽  
Disease Severity ◽  
Viral Entry ◽  
Thrombus Formation ◽  
Clinical Findings ◽  
High Risk Group ◽  
Therapeutic Interventions ◽  
Cytokine Storm ◽  
Negative Consequences ◽  
Major Complications

Emerging data suggest that obesity is a major risk factor for the progression of major complications such as acute respiratory distress syndrome (ARDS), cytokine storm and coagulopathy in COVID-19. Understanding the mechanisms underlying the link between obesity and disease severity as a result of SARS-CoV-2 infection is crucial for the development of new therapeutic interventions and preventive measures in this high-risk group. We propose that multiple features of obesity contribute to the prevalence of severe COVID-19 and complications. First, viral entry can be facilitated by the upregulation of viral entry receptors, like angiotensin-converting enzyme 2 (ACE2), among others. Second, obesity-induced chronic inflammation and disruptions of insulin and leptin signaling can result in impaired viral clearance and a disproportionate or hyper-inflammatory response, which together with elevated ferritin levels can be a direct cause for ARDS and cytokine storm. Third, the negative consequences of obesity on blood coagulation can contribute to the progression of thrombus formation and hemorrhage. In this review we first summarize clinical findings on the relationship between obesity and COVID-19 disease severity and then further discuss potential mechanisms that could explain the risk for major complications in patients suffering from obesity.

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