A new way to treat proximal deep venous thrombosis using E-selectin inhibition.
Animal models
Coagulation
E-selectin inhibition
Glycomimetic
Inflammation
Nonhuman primate
Venous thrombosis
Journal
Journal of vascular surgery. Venous and lymphatic disorders
ISSN: 2213-3348
Titre abrégé: J Vasc Surg Venous Lymphat Disord
Pays: United States
ID NLM: 101607771
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
23
04
2019
accepted:
16
08
2019
entrez:
19
2
2020
pubmed:
19
2
2020
medline:
15
9
2020
Statut:
ppublish
Résumé
There is an inter-relationship between thrombosis and inflammation. Previously, we have shown the importance of P-selectin in thrombogenesis and thrombus resolution in many preclinical animal models. The role of E-selectin has been explored in rodent models and in a small pilot study of clinical calf vein deep venous thrombosis. The purpose of this study was to determine the role of E-selectin in thrombosis in a primate model of proximal iliac vein thrombosis, a model close to the human condition. Iliac vein thrombosis was induced with a well-characterized primate model. Through a transplant incision, the hypogastric vein and iliac vein branches were ligated. Thrombus was induced by balloon occlusion of the proximal and distal iliac vein for 6 hours. The balloons were then deflated, and the primates recovered. Starting on postocclusion day 2, animals were treated with the E-selectin inhibitor GMI-1271, 25 mg/kg subcutaneously, once daily until day 21 (n = 4). Nontreated control animals received no treatment (n = 5). All animals were evaluated by magnetic resonance venography (MRV); evaluation of vessel area by ultrasound, protein analysis, hematology (complete blood count), and coagulation tests (bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, and thromboelastography) were performed at baseline, day 2, day 7, day 14, and day 21 with euthanasia. In addition, platelet function and CD44 expression on leukocytes were determined. E-selectin inhibition by GMI-1271 significantly increased vein recanalization by MRV vs control animals on day 14 (P < .05) and day 21 (P < .0001). GMI-1271 significantly decreased vein wall inflammation by MRV with gadolinium vein wall enhancement vs control also on day 14 (P < .0001) and day 21 (P < .0001). The thromboelastographic measure of clot strength (maximum amplitude) showed significant decreases in animals treated with GMI-1271 vs controls at day 2 (P < .05) and day 7 (P < .05). Animals treated with GMI-1271 had significant vessel area increase by day 21 vs controls (P < .05) by ultrasound. Vein wall intimal thickening (P < .001) and intimal fibrosis (P < .05) scores were significantly decreased in GMI-1271-treated animals vs controls. Importantly, no significant differences in hematology or coagulation test results were noted between all groups, suggesting that E-selectin inhibition carries no bleeding potential. GMI-1271 did not affect platelet function or aggregation or CD44 expression on leukocytes. In addition, no episodes of bleeding were noted in either group. This study suggests that E-selectin modulates venous thrombus progression and that its inhibition will increase thrombus recanalization and decrease vein wall inflammation, without affecting coagulation. The use of an E-selectin inhibitor such as GMI-1271 could potentially change how we treat deep venous thrombosis.
Identifiants
pubmed: 32067728
pii: S2213-333X(19)30496-2
doi: 10.1016/j.jvsv.2019.08.016
pmc: PMC9006622
mid: NIHMS1569168
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
E-Selectin
0
Fibrinolytic Agents
0
Glycolipids
0
uproleselan
PE952ANF83
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
268-278Subventions
Organisme : NHLBI NIH HHS
ID : HHSN268201700004C
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
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