Advances in understanding the molecular mechanisms of venous thrombosis

Preston, Roger J. S.; O’Sullivan, Jamie M.; O’Donnell, James S.

doi:10.1111/bjh.15869

Cited by 38 publications

(24 citation statements)

References 106 publications

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“…10 The main function of the flow diverter is to reduce blood flow and stasis in the aneurysm so that gradual thrombosis occurs within the aneurysm and subsequent healing. 11,12 The aneurysm sac is prone to thrombosis because of the irregular patterns of blood flow and the potential for a low oxygen tension, especially during immobilization or long-haul travel. 13 Early and delayed aneurysm ruptures following treatment with PFS have been analyzed by Lv et al 14 Although the definite causes of the aneurysm rupture are not yet proved, they suggested aggressive aneurysm thrombosis resulting in acute aneurysm growth cause of the delayed aneurysm rupture following flow-diverter treatment.…”

Section: Discussionmentioning

confidence: 99%

Complex cerebral aneurysms: intra-luminal reconstruction using Pipeline flow-diverting stent and the obliteration mechanism

Jiang

et al. 2019

Neuroradiol J

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Objectives Patients with complex cerebral aneurysms can now be treated intravascularly with the help of flow-diverting stents. The primary purpose of this article is to document the clinical and angiographic outcomes in 80 patients who were treated with the Pipeline flow-diverting stent (PFS; Medtronic, Dublin, Ireland) and the obliteration mechanism was discussed. Patients and methods Between October 2015 and October 2019, 80 patients with 90 complex (undefined neck, large/giant, blood blister–like, and recurrent side-wall) cerebral aneurysms treated with the PFS were retrospectively reviewed. Forty-five patients were women and 35 were men, with a mean age of 52 years. Large or giant aneurysms were defined as 10 mm or larger and small aneurysms were defined as less than 10 mm at the largest diameter measured on angiogram. Results Forty-one aneurysms (45.6%) were large or giant, 41 (45.6%) were small, four (4.4%) were recurrent side-wall aneurysms and four (4.4%) were blood blister–like aneurysms. In total, 87 PFSs were placed in 80 patients with 90 aneurysms. In six patients, coexisting proximal stenosis of parent artery was also covered with PFS without balloon angioplasty. Adjunct coils were placed in 31 aneurysms (34%). One patient died of intracerebral hematoma after thrombolysis. There was one intrastent occlusion at six-month follow-up without any symptoms. The morbidity and the mortality rate is 0% and 1.3% (95% confidence interval (CI), 0%–3.7%). Control angiography was available in 74 (92.5%) patients with 83 aneurysms, and the aneurysm occlusion rate was 98.8% (95% CI, 96.5%–100%) in 6 to 12 months. Conclusion For wide-necked saccular, large/giant, blood blister–like aneurysms and recurrent side-wall aneurysms, PFS is a valid and safe treatment option.

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Section: Discussionmentioning

confidence: 99%

Complex cerebral aneurysms: intra-luminal reconstruction using Pipeline flow-diverting stent and the obliteration mechanism

Jiang

et al. 2019

Neuroradiol J

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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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“…Consequently, an alternative approach to restoring hemostatic balance in PWH is through targeted inhibition of specific anticoagulant pathways. Antithrombin (AT) is plasma serine protease inhibitor (serpin) that regulates the procoagulant activity of a number of activated clotting factors, including thrombin and activated factor X (FXa; Preston et al , ; Fig ). Patients with inherited antithrombin deficiency have significantly increased risk of venous thromboembolism (VTE).…”

Section: Targeted Inhibition Of Antithrombin Anticoagulant Effect By mentioning

confidence: 99%

Antithrombin inhibition using nanobodies to correct bleeding in hemophilia

O’Sullivan

O’Donnell

2020

EMBO Mol Med

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In this issue of EMBO Molecular Medicine, Barbon et al describe a new approach to rebalancing coagulation in patients with hemophilia (PWH) through targeted inhibition of anticoagulant antithrombin (AT) (Barbon et al, 2020). In contrast to previous studies that used RNA interference (RNAi) therapy to reduce AT levels (Sehgal et al, 2015; Pasi et al, 2017), the authors utilized llama‐derived single‐domain antibodies (sdAbs or nanobodies) to inhibit AT activity (Fig 1). These engineered sdAbs successfully restored thrombin generation in hemophilic plasma and corrected bleeding phenotype in a murine hemophilia model. Furthermore, long‐term AAV8‐mediated hepatic expression of the sdAb was well tolerated and associated with a sustained correction in bleeding in hemophilia A and B mice. Collectively, these exciting data uncover a novel AT‐targeting approach that may be useful as an alternative therapy for restoring normal hemostasis in PWH.

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Advances in understanding the molecular mechanisms of venous thrombosis

Cited by 38 publications

References 106 publications

Complex cerebral aneurysms: intra-luminal reconstruction using Pipeline flow-diverting stent and the obliteration mechanism

Complex cerebral aneurysms: intra-luminal reconstruction using Pipeline flow-diverting stent and the obliteration mechanism

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Antithrombin inhibition using nanobodies to correct bleeding in hemophilia

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