Stimulate Thrombus Formation Research Articles

Computational study of clot formation in aneurysms treated with shape memory polymer foam

To prevent aneurysmal rupture, intracranial aneurysms are often treated with endovascular metal coils that fill the aneurysm sac and stimulate thrombus formation, thereby isolating the aneurysm from the arterial flow. Despite its widespread use, this method can result in suboptimal outcomes leading to aneurysm recurrence. Recently, shape memory polymer foam has been proposed as an alternative aneurysm filler. In this work, a computational thrombus model is used to predict the clotting response within idealized 2D aneurysms virtually treated with foam. The results are compared to previously reported clot formation predictions in identical 2D aneurysm geometries filled with simplified endovascular metal coil shapes. Each of the foam-filled aneurysms reached at least 94% thrombus occlusion regardless of foam pore size or orientation, whereas the final thrombus occlusion within the coil-filled aneurysms varied from 80.8 to 92.2% with many of the cases leaving large areas in the aneurysm neck unfilled. Based on the simulations presented here, shape memory polymer foams may be able to produce more predictable, uniform, and complete clotting results than bare metal coils, independent of foam geometry or orientation.

Flow Patterns in Carotid Webs: A Patient-Based Computational Fluid Dynamics Study.

Carotid webs are increasingly recognized as an important cause of (recurrent) ischemic stroke in patients without other cardiovascular risk factors. Hemodynamic flow patterns induced by these lesions might be associated with thrombus formation. The aim of our study was to evaluate flow patterns of carotid webs using computational fluid dynamics. Patients with a carotid web in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) were selected for hemodynamic evaluation with computational fluid dynamics models based on lumen segmentations obtained from CT angiography scans. Hemodynamic parameters, including the area of recirculation zone, time-averaged wall shear stress, transverse wall shear stress, and the oscillatory shear index, were assessed and compared with the contralateral carotid bifurcation. In our study, 9 patients were evaluated. Distal to the carotid webs, recirculation zones were significantly larger compared with the contralateral bifurcation (63 versus 43 mm2, P = .02). In the recirculation zones of the carotid webs and the contralateral carotid bifurcation, time-averaged wall shear stress values were comparable (both: median, 0.27 Pa; P = .30), while transverse wall shear stress and oscillatory shear index values were significantly higher in the recirculation zone of carotid webs (median, 0.25 versus 0.21 Pa; P = .02 and 0.39 versus 0.30 Pa; P = .04). At the minimal lumen area, simulations showed a significantly higher time-averaged wall shear stress in the web compared with the contralateral bifurcation (median, 0.58 versus 0.45 Pa; P = .01). Carotid webs are associated with increased recirculation zones and regional increased wall shear stress metrics that are associated with disturbed flow. These findings suggest that a carotid web might stimulate thrombus formation, which increases the risk of acute ischemic stroke.

Numerical Simulation of Thrombotic Occlusion in Tortuous Arterioles

Tortuous microvessels alter blood flow and stimulate thrombosis but the physical mechanisms are poorly understood. Both tortuous microvessels and abnormally large platelets are seen in diabetic patients. Thus, the objective of this study was to determine the physical effects of arteriole tortuosity and platelet size on the microscale processes of thrombotic occlusion in microvessels. A new lattice-Boltzmann method-based discrete element model was developed to simulate the fluid flow field with fluid-platelet coupling, platelet interactions, thrombus formation, and thrombotic occlusion in tortuous arterioles. Our results show that vessel tortuosity creates high shear stress zones that activate platelets and stimulate thrombus formation. The growth rate depends on the level of tortuosity and the pressure and flow boundary conditions. Once thrombi began to form, platelet collisions with thrombi and subsequent activations were more important than tortuosity level. Thrombus growth narrowed the channel and reduced the flow rate. Larger platelet size leads to quicker decrease of flow rate due to larger thrombi that occluded the arteriole. This study elucidated the important roles that tortuosity and platelet size play in thrombus formation and occlusion in arterioles.

Ticagrelor: a novel drug for an old problem.

Cardiovascular disease and in particular, acute coronary syndromes are one of the principle causes of death in the industrialized countries. In the setting of acute coronary syndromes (both ST - segment or non ST - segment elevation myocardial infarction), platelets aggregation plays a key and central role in their development. Platelets are the mediators of hemostasis 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. Recent patent relates to the methods and devices for treating atherosclerosis and to prevent in-stent restenosis or thrombosis. Because of the importance of platelets involvement in the initiation and propagation of thrombosis, antiplatelet drugs have a source of research; in the recent past, new antiplatelet drugs (such as ticagrelor) have been studied and placed in the routine therapy. The aim of this paper is to summarize the pharmacological properties and the clinical characteristics of ticagrelor.

Finite Element Model and Fluid-Structure Interaction Analysis of the Intravascular Stent

The 316L stainless steel stent was analyzed about the effect on interaction with plaque and vessels and blood flow during and after implantation using finite element method (FEM) and computational fluid dynamics (CFD). The results showed that tilted ends are likely to damage the intima which may stimulate thrombus formation and neointimal hyperplasia and will cause the restenosis. Stagnant zones formed by the stent may cause the backflow phenomenon, which also contribute to the important elements of in-stent restenosis (ISR).

Neutrophil Extracellular Trap (NET) Impact on Deep Vein Thrombosis

Deep vein thrombosis (DVT) is a major health problem that requires improved prophylaxis and treatment. Inflammatory conditions such as infection, cancer, and autoimmune diseases are risk factors for DVT. We and others have recently shown that extracellular DNA fibers produced in inflammation and known as neutrophil extracellular traps (NETs) contribute to experimental DVT. NETs stimulate thrombus formation and coagulation and are abundant in thrombi in animal models of DVT. It appears that, in addition to fibrin and von Willebrand factor, NETs represent a third thrombus scaffold. Here, we review how NETs stimulate thrombosis and discuss known and potential interactions of NETs with endothelium, platelets, red blood cells, and coagulation factors and how NETs could influence thrombolysis. We propose that drugs that inhibit NET formation or facilitate NET degradation may prevent or treat DVT.

Antiplatelet therapy: thrombin receptor antagonists

Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. Multiple pathways contribute to platelet activation. Aspirin, an irreversible inhibitor of thromboxane A2 synthesis, in combination with clopidogrel, an inhibitor of P2Y(12) adenosine diphosphate platelet receptors, represent the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations. Thrombin is one of the most important platelet activators. The inhibition of protease-activated receptor 1 showed a good safety profile in preclinical studies. In fact, phase II studies with vorapaxar (SCH530348) and atopaxar (E5555) showed no increase of bleeding events in addition to the current standard-of-care of antiplatelet therapy. Although the results of phase III trials for both drugs are awaited, this family is a promising new addition to the current clinical practice for patients with atherothrombotic disease, not only as an alternative, but also as additional therapy.

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

Platelets 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 P2Y(12) adenosine diphosphate (ADP) receptor antagonist target the thromboxane A(2) 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.

Insulin Resistance Affects Gene Expression in Endothelium

To the editor: We and others have found that either genetic insulin resistance or hyperinsulinemia may dampen insulin ability to activate the PI3-kinase/Akt pathway, leading to perturbation of endothelial nitric oxide synthase (eNOS) activation.1,2 However, little is known about insulin effects on transcription of antiatherogenic and proatherogenic genes in insulin resistant conditions. Therefore, we used a genetic model of vascular insulin resistance, primary human umbilical vein endothelial cells (HUVECs) naturally carrying the G972R Insulin Receptor Substrate-1 (IRS-1) variant,2 to investigate the effect of both genetic insulin resistance and hyperinsulinemia on transcription of atherosclerosis related genes. G972R IRS-1 variant reduces IRS-1 activation of the PI3-K/Akt pathway,3 and it has been associated to coronary artery disease and obesity.3,4 HUVECs carrying the wild-type (WT) or G972R IRS-1 variant were obtained as previously described.3 For the experiments, 3rd through 5th passage HUVEC-WT and 972 were incubated in serum free EGM-2 medium for 16 hours in the presence or absence of insulin 5×10−7 mol/L, to obtain a full effect of insulin on nitric oxide production.5 Total RNA was extracted from the HUVECs with Trizol reagent according to the manufacturer’s protocol. To profile gene expression pattern we made use of U133A Affymetrix DNA microarray containing a total number of 22283 probe sets corresponding to about 15 000 genes, using previously described methods.6 Gene expression profiling was obtained by …

COADMINISTRATION OF LOW-DOSE LIPOPOLYSACCHARIDE AND SOLUBLE TISSUE FACTOR INDUCES THROMBOSIS AFTER RADIOSURGERY IN AN ANIMAL ARTERIOVENOUS MALFORMATION MODEL

Radiosurgery for arteriovenous malformations is limited to small lesions and may take 3 years to produce total occlusion. It has recently been shown that coadministration of low-dose lipopolysaccharide (LPS) and soluble tissue factor (sTF) selectively induces thrombosis in murine tumor models, attributable perhaps to the prothrombotic phenotype of tumor vasculature. Radiosurgery may induce changes in endothelial prothrombotic molecules similar to those found in tumors. This study aimed to determine if a similar strategy could be used to stimulate thrombus formation in an animal arteriovenous malformation model. Seventeen rats underwent creation of a carotid-to-jugular anastomosis. Animals were intravenously injected with sTF, low-dose LPS, a combination of both, or placebo 24 hours after stereotactic irradiation of the anastomosis. Control animals received both agents after sham irradiation. Coadministration of sTF and LPS led to the formation of thrombi in up to 69% of small vessels and 39% of medium-sized vessels within the target region. The irradiated vasculature demonstrated intermediate rates of thrombosis after treatment with either sTF or LPS alone as did vessels within the fistula in the control group. Logistic regression analysis demonstrated significant associations between development of thrombi and treatment with radiation, sTF, or LPS (P < 0.005). There was no evidence of systemic thrombus formation or toxicity in any group. Treatment with sTF and LPS selectively induces thrombosis of irradiated vessels in a rat model of arteriovenous malformation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing the treatable lesion size and reducing latency.

Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI

Lipid-rich atherosclerotic plaques are vulnerable, and their rupture can cause the formation of a platelet- and fibrin-rich thrombus leading to myocardial infarction and ischemic stroke. Although the role of plaque-based tissue factor as stimulator of blood coagulation has been recognized, it is not known whether plaques can cause thrombus formation through direct activation of platelets. We isolated lipid-rich atheromatous plaques from 60 patients with carotid stenosis and identified morphologically diverse collagen type I- and type III-positive structures in the plaques that directly stimulated adhesion, dense granule secretion, and aggregation of platelets in buffer, plasma, and blood. This material also elicited platelet-monocyte aggregation and platelet-dependent blood coagulation. Plaques exposed to flowing blood at arterial wall shear rate induced platelets to adhere to and spread on the collagenous structures, triggering subsequent thrombus formation. Plaque-induced platelet thrombus formation was observed in fully anticoagulated blood (i.e., in the absence of tissue factor-mediated coagulation). Mice platelets lacking glycoprotein VI (GPVI) were unable to adhere to atheromatous plaque or form thrombi. Human platelet thrombus formation onto plaques in flowing blood was completely blocked by GPVI inhibition with the antibody 10B12 but not affected by integrin alpha2beta1 inhibition with 6F1 mAb. Moreover, the initial platelet response, shape change, induced by plaque was blocked by GPVI inhibition but not with alpha2beta1 antagonists (6F1 mAb or GFOGER-GPP peptide). Pretreatment of plaques with collagenase or anti-collagen type I and anti-collagen type III antibodies abolished plaque-induced platelet activation. Our results indicate that morphologically diverse collagen type I- and collagen type III-containing structures in lipid-rich atherosclerotic plaques stimulate thrombus formation by activating platelet GPVI. This platelet collagen receptor, essential for plaque-induced thrombus formation, presents a promising new anti-thrombotic target for the prevention of ischemic cardiovascular diseases.

Testosterone inhibits prostacyclin production by rat aortic smooth muscle cells in culture

The effects of testosterone on cell proliferation and prostacyclin production were investigated using rat aortic smooth muscle cells in culture. Testosterone at 10 −10 – 10 −6 M did not have any significant effect on cell proliferation, but it significantly inhibited prostacyclin production by the cells. Maximal inhibition of prostacyclin production (70%) was observed when cells were treated with a physiological concentration of 10 −8M testosterone for 5 consecutive days. These results suggest that testosterone may stimulate thrombus formation and accelerate atherosclerosis by suppressing prostacyclin production in arterial smooth muscle cells.