E-selectin inhibition with GMI-1271 decreases venous thrombosis without profoundly affecting tail vein bleeding in a mouse model

Culmer, Dorian Laird; Dunbar, Misha; Hawley, Angela E.; Sood, Suman L.; Sigler, Robert E.; Henke, Peter K.; Wakefield, Thomas W.; Magnani, John L.; Myers, Daniel D.

doi:10.1160/th16-04-0323

Cited by 33 publications

(29 citation statements)

References 44 publications

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“…P-selectin inhibition has been shown to decrease venous thrombosis in murine ( 64 ) thrombosis models and enhance thrombus resolution in rat models ( 65 ). Similarly, E-selectin inhibition with a small molecule inhibitor has been shown to decrease inflammation (vein wall monocyte extravasation) and acute venous thrombosis in a surgical model of murine thrombosis induction ( 66 ) and is now being studied in early clinical trials in humans.…”

Section: Surgery and Traumamentioning

confidence: 99%

The Role of Inflammation in Venous Thromboembolism

2018

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Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT), and pulmonary embolism (PE), is becoming increasingly recognized as a cause of morbidity and mortality in pediatrics, particularly among hospitalized children. Furthermore, evidence is accumulating that suggests the inflammatory response may be a cause, as well as consequence, of VTE, but current anticoagulation treatment regimens are not designed to inhibit inflammation. In fact, many established clinical VTE risk factors such as surgery, obesity, cystic fibrosis, sepsis, systemic infection, cancer, inflammatory bowel disease, and lupus likely modulate thrombosis through inflammatory mediators. Unlike other traumatic mechanisms of thrombosis involving vascular transection and subsequent exposure of subendothelial collagen and other procoagulant extracellular matrix materials, inflammation of the vessel wall may initiate thrombosis on an intact vein. Activation of endothelial cells, platelets, and leukocytes with subsequent formation of microparticles can trigger the coagulation system through the induction of tissue factor (TF). Identification of biomarkers to evaluate VTE risk could be of great use to the clinician caring for a patient with inflammatory disease to guide decisions regarding the risk:benefit ratio of various types of potential thromboprophylaxis strategies, or suggest a role for anti-inflammatory therapy. Unfortunately, no such validated inflammatory scoring system yet exists, though research in this area is ongoing. Elevation of C-reactive protein, IL-6, IL-8, and TNF-alpha during a response to systemic inflammation have been associated with increased VTE risk. Consequent platelet activation enhances the prothrombotic state, leading to VTE development, particularly in patients with other risk factors, most notably central venous catheters.

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Section: Surgery and Traumamentioning

confidence: 99%

The Role of Inflammation in Venous Thromboembolism

2018

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“…Cell adhesion modules, which were initially understood in the context of venous thrombogenesis [143], are also significant predictors for post-thrombotic resolution [120,144,145] These include P-selectin [146][147][148] and E-selectin [149,150], which are receptors on endothelial cells that specifically bind and activate immune cells in early thrombogenesis and are elevated in acute DVT. Inhibition of these selectins both prophylactically and as a post-thrombotic treatment improved DVT resolution.…”

Section: Endothelial Cellsmentioning

confidence: 99%

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Nicklas

Gordon

Henke

2020

IJMS

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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. already progressed past the point of anticoagulant efficacy [12,13]. Thus, there is potential clinical utility in investigating and controlling the process by which DVTs resolve in order to provide better care to these later-stage patients, with less bleeding risk. Overview of Venous Thrombus Development in HumansThe time sequence of DVT development and resolution was correctly suggested as early as 1962, based on empirical stains that detected changes in the nanoscopic roughness of clotted material [14]. As Lendrum et. al. remarked, "we consider that the intracytoplasmic granules, which we think are engulfed fibrin, seen in pulmonary phagocytes and in the endothelium of arteries and veins containing thrombus, are better shown by this (methyl-scarlet-blue) method than by any of the others." In fresh clot (whether in deep veins or in diabetic kidneys), platelets and erythrocytes are initially linked in a fine mesh yielding a relatively smooth surface (stage 1). A mat of the medium-textured fibrin replaces the initial thrombus (stage 2), which is gradually replaced by much coarser collagen (stage 3). This staging of clot development quickly became the basis of a pathological guide to grade thrombi [15]. The current three-stage refinement of the DVT grading scheme indicates that the turnover of erythrocyte-rich to fibrin-rich clot in humans is complete approximately seven days after the initial thrombotic event [16], whereas fibrin deposition commences after one day [17]. Various leukocytes, initially neutrophils and later macrophages, are believed to control this progression of DVTs development from a mass of erythrocytes, to fibrin, and finally to collagen [18]. Infiltrating T-lymphocytes and macrophages conta...

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“…It is evident that the interplay between neutrophil, endothelial and platelet activation cannot be reduced to a single initiator of thrombosis, vessel stenosis or tissue fibrosis. Therefore, while blocking neutrophil-vessel interactions has shown therapeutic promise in reducing neutrophil-mediated vessel damage [81,[88][89][90][91][92], pro-inflammatory neutrophil-platelet interactions are a compelling target for emerging therapeutics [93].…”

Section: Link To the Inflammatory Trianglementioning

confidence: 99%

Endothelial cells, neutrophils and platelets: getting to the bottom of an inflammatory triangle

Dehghani

Panitch

2020

Open Biol.

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Severe fibrotic and thrombotic events permeate the healthcare system, causing suffering for millions of patients with inflammatory disorders. As late-state consequences of chronic inflammation, fibrosis and thrombosis are the culmination of pathological interactions of activated endothelium, neutrophils and platelets after vessel injury. Coupling of these three cell types ensures a pro-coagulant, cytokine-rich environment that promotes the capture, activation and proliferation of circulating immune cells and recruitment of key pro-fibrotic cell types such as myofibroblasts. As the first responders to sterile inflammatory injury, it is important to understand how endothelial cells, neutrophils and platelets help create this environment. There has been a growing interest in this intersection over the past decade that has helped shape the development of therapeutics to target these processes. Here, we review recent insights into how neutrophils, platelets and endothelial cells guide the development of pathological vessel repair that can also result in underlying tissue fibrosis. We further discuss recent efforts that have been made to translate this knowledge into therapeutics and provide perspective as to how a compound or combination therapeutics may be most efficacious when tackling fibrosis and thrombosis that is brought upon by chronic inflammation.

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E-selectin inhibition with GMI-1271 decreases venous thrombosis without profoundly affecting tail vein bleeding in a mouse model

Cited by 33 publications

References 44 publications

The Role of Inflammation in Venous Thromboembolism

The Role of Inflammation in Venous Thromboembolism

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Endothelial cells, neutrophils and platelets: getting to the bottom of an inflammatory triangle

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