Neutrophils Are the Initial Cell Type Identified in Deep Venous Thrombosis Induced Vein Wall Inflammation

Downing, L.; Strieter, Robert M.; Kadell, Amy M.; Wilke, Carol A.; Brown, Sandra L.; Wrobleski, Shirley K.; Burdick, Marie D.; Hulin, Marc S.; Fowlkes, J. Brian; Greenfield, Lazar J.; Wakefield, Thomas W.

doi:10.1097/00002480-199609000-00073

Cited by 45 publications

(34 citation statements)

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“…VTE is a condition associated with an apparently excessive free radical production not buffered by efficient defense systems. Evidence was also provided of immunohistochemical detection of (MPO)-positive neutrophils in venous thrombi [46,47]. These findings encouraged a clinical study aimed to assess the sequential combinations of DD and MPO, and DD and CRP in a prospective sample of 304 ED patients evaluated for PE as compared to DD alone.…”

Section: The Presentmentioning

confidence: 99%

Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future

Lippi

Cervellin

Franchini

et al. 2010

J Thromb Thrombolysis

106

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Deep venous thrombosis and pulmonary embolism represent two expressions of a similar clinical pathological process traditionally referred to as venous thromboembolism. Several population studies evidence venous thromboembolism as a leading healthcare problem worldwide, highlighting the need for early and reliable diagnosis to enable appropriate triage of affected patients and to optimize outcome. There is still debate, however, on which thrombotic markers to use, as well as their most suitable position within diagnostic algorithms. This article aims to review the pathophysiology and clinical usefulness of past, present and future markers of thrombosis, including soluble fibrin monomers, fibrin/fibrinogen degradation products, thrombin-antithrombin complex, plasmin-antiplasmin complex, fibrinopeptide A and B, prothrombin fragments 1 + 2, thrombus precursor protein, D-dimer, activated protein C-protein C inhibitor complex, myeloperoxidase, thrombin generation assays and proteomic analysis. Several lines of evidence now attest that the global diagnostic performances of some D-dimer assays largely outperform those of any other coagulation or fibrinolytic marker proposed thus far, and a "negative" D-dimer measured with rapid enzyme linked fluorescent immunoassay is now considered the biochemical gold standard for ruling out an acute episode of venous thromboembolism in a patient with a low pretest probability for venous thromboembolism, so that additional testing can be safely omitted. However, to further improve clinical outcomes, the diagnostic efficiency of combining D-dimer testing with other markers covering different pathophysiological aspects of thrombosis such as continuous and progressive thrombin generation (e.g., activated protein C-protein C inhibitor complex) or neutrophil activation (i.e., myeloperoxidase) merits further investigation. Proteomic analysis, which would help to characterize the structure and function of each protein and the complexities of protein-protein interactions in physiological and pathological hemostasis, also holds promise for identifying novel markers and developing effective diagnostic protocols in the future.

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Section: The Presentmentioning

confidence: 99%

Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future

Lippi

Cervellin

Franchini

et al. 2010

J Thromb Thrombolysis

106

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“…39 Bivalirudin also decreased reperfusion time when given with tissue-type plasminogen activator as a thrombolytic to aortic thrombi in rats. Bivalirudin also decreased 111 In-oxine-labeled platelet accumulation in the brain after intracarotid injection of thrombin to rabbits. In this model, it was compared with aspirin and with heparin.…”

Section: Bivalirudin (1999; Nda 20-873)mentioning

confidence: 81%

“…Finally, eptifibitide improved platelet count and platelet function after a hypothermic cardiopulmonary bypass in dogs. In baboons, eptifibitide reduced the accumulation of 111 In-oxine-labeled platelets on a Dacron graft in a femoral arteriovenous shunt model. This effect was not increased by heparin or aspirin.…”

Section: Eptifibitide (1987; Nda 20-718)mentioning

confidence: 92%

“…In recent work, it was found that neutrophils, monocytes, and platelets interact in the developing venous thrombus to promote clot formation, 110 a finding confirming early work in a similar rat version of the IVC stasis model. 110 Neutrophil extracellular traps, extruded nucleic acids and histones from localized neutrophils, have been shown to promote venous thrombus growth in the IVC stenosis model, 111 with histone modification influencing this process.…”

Section: Use Of Venous Thrombosis Modelsmentioning

confidence: 99%

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Animal Models of Thrombosis From Zebrafish to Nonhuman Primates

Jagadeeswaran

Cooley

Gross

et al. 2016

Circulation Research

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Thrombosis is a leading cause of morbidity and mortality worldwide. Animal models are used to understand the pathological pathways involved in thrombosis and to test the efficacy and safety of new antithrombotic drugs. In this review, we will first describe the central role a variety of animal models of thrombosis and hemostasis has played in the development of new antiplatelet and anticoagulant drugs. These include the widely used P2Y 12 antagonists and the recently developed orally available anticoagulants that directly target factor Xa or thrombin. Next, we will describe the new players, such as polyphosphate, neutrophil extracellular traps, and microparticles, which have been shown to contribute to thrombosis in mouse models, particularly venous thrombosis models. Other mouse studies have demonstrated roles for the factor XIIa and factor XIa in thrombosis. This has spurred the development of strategies to reduce their levels or activities as a new approach for preventing thrombosis. Finally, we will discuss the emergence of zebrafish as a model to study thrombosis and its potential use in the discovery of novel factors involved in thrombosis and hemostasis. Animal models of thrombosis from zebrafish to nonhuman primates are vital in identifying pathological pathways of thrombosis that can be safely targeted with a minimal effect on hemostasis. Future studies should focus on understanding the different triggers of thrombosis and the best drugs to prevent each type of thrombotic event. (Circ Res.

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“…19) Regarding vein wall disorders in the process of thrombogenesis, Downing et al reported a significant increase in the number of neutrophils infiltrating the vein wall after 6 h in a rat IVC ligation model, suggesting functional damage to the vein wall and the accelerated formation of a thrombus. 20) We also previously showed that a pretreatment for venous thrombosis with P-selectin blockade using glycyrrhizin, a carbohydrate analogous to the selectin ligand sialyl-Lewis X and glycomimetics, was beneficial for reducing neutrophil adhesion, thereby preventing the formation of venous thrombosis associated with IVC ligation for 6 h in rats. 6) Liver antithrombin mRNA expression levels were significantly higher in the ligated groups: the glycyrrhizintreated, fondaparinux-treated, and saline-treated groups, than in the baseline control group.…”

Section: Discussionmentioning

confidence: 96%

Effects of Preoperative Glycyrrhizin Infusion for the Prevention of Venous Thrombosis on the Tissue Expression of Antithrombin in a Rat Model

Nakata¹,

Kira

2016

Annals of Vascular Diseases

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Objective: Using a thrombus model prepared by ligation of the inferior vena cava (IVC), the influences of the glycoside, glycyrrhizin, on plasma antithrombin levels and antithrombin mRNA expression levels in the liver and IVC with the inhibition of venous thrombosis were investigated. Materials and Methods: The rat IVC was exposed and ligated for 24 h immediately after the intravenous administration of 300 mg/kg glycyrrhizin. Among antithrombotic drugs, the Xa inhibitor, fondaparinux sodium, was used as a control drug. Results: The mean thrombus weight was significantly smaller in the glycyrrhizin-treated group (18.3 mg) than in the salinetreated group (34.3 mg). In contrast, the inhibition of thrombosis was not observed in the fondaparinux-treated group. Antithrombin mRNA expression levels in the liver were significantly higher in the ligated groups than in the baseline control group. The mean plasma antithrombin level was significantly lower in the glycyrrhizin group (96.6%) than in the saline group (114.4%), but was not significantly different from that in the baseline control group (102.4%). Conclusion:The pretreatment with glycyrrhizin inhibited venous thrombosis, and antithrombin mRNA expression levels in the liver and IVC as well as plasma antithrombin levels were significantly lower than those in the saline group.Keywords: glycyrrhizin, antithrombin, DVT targets being thrombin, factor Xa, and factor IXa. A sequence-specific pentasaccharide present in only a fraction of heparin molecules mediates the high-affinity binding and anticoagulant activation of antithrombin by this polysaccharide. 1) Antithrombin has lysine binding sites to which heparin binds at a molar ratio of 1:1. The half-life of thrombin is reduced to 20 ms in the presence of a high concentration of heparin, which is an approximately 2000-fold acceleration of this reaction. 2) Griffith previously identified thrombin-heparin binding as the most important factor for efficient thrombin inhibition by antithrombin. 3) P-and E-selectins have been known to mediate the linkage of endothelial cells to neutrophils through the binding to sialyl-Lewis X glycoproteins, which are expressed on the surface of neutrophils. 4,5) Neutrophils adherent to the endothelium also undergo transendothelial migration, leading to endothelial cell sloughing and exposure of the underlying basement membrane to the accelerated formation of deep vein thrombosis (DVT). 6) Glycyrrhizin, which is a natural triterpenoid saponin with a molecular mass of 840 Daltons, has been approved for useful drug for the treatment of allergic disorders and chronic hepatitis in Japan. We previously showed that glycyrrhizin was effective on the prevention of the tissue damage caused by ischemia-reperfusion in the rabbit hind limb. 7) were the first to demonstrate that glycyrrhizin exhibits antithrombotic activity in vivo and, it has, thus, been characterized as a potential thrombin inhibitor. Assafim et al. 9) showed that glycyrrhizin was effective in preventing venom-induced thrombus formati...

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Neutrophils Are the Initial Cell Type Identified in Deep Venous Thrombosis Induced Vein Wall Inflammation

Cited by 45 publications

References 0 publications

Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future

Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future

Animal Models of Thrombosis From Zebrafish to Nonhuman Primates

Effects of Preoperative Glycyrrhizin Infusion for the Prevention of Venous Thrombosis on the Tissue Expression of Antithrombin in a Rat Model

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