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Thromb Haemost 2017; 117(06): 1171-1181
DOI: 10.1160/TH16-04-0323
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

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

Dorian L. Culmer
1   Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
,
Misha L. Dunbar
2   Research Animal Resources, University of Minnesota, Minneapolis, Minnesota, USA
,
Angela E. Hawley
3   Department of Surgery, Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Suman Sood
4   Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Robert E. Sigler
5   Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Peter K. Henke
3   Department of Surgery, Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Thomas W. Wakefield
3   Department of Surgery, Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
John L. Magnani
6   GlycoMimetics Inc., Rockville, Maryland, USA
,
Daniel D. Myers Jr.
3   Department of Surgery, Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
5   Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
› Author Affiliations
Further Information

Publication History

Received: 23 April 2016

Accepted after major revision: 21 February 2017

Publication Date:
09 November 2017 (online)

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Summary

Selectins, such as E-selectin (CD62E), function in venous thrombosis by binding and activating immune cells to initiate the coagulation cascade. GMI-1271 is a small molecule antagonist that inhibits E-selectin activity. Here we determine whether inhibition of E-selectin is sufficient to decrease acute venous thrombosis and associated inflammatory events in both prophylactic and treatment protocols without significantly affecting haemostasis. Male C57BL/6 mice underwent surgery for experimental thrombosis induction and were harvested at peak thrombus formation in our animal model, two days post induction. Groups included non-thrombosed true controls, shams, controls, and prophylactic or treatment groups of GMI-1271 (10 mg/kg intraperitoneal BID (twice a day) and low-molecular-weight heparin (LMWH, Lovenox 6 mg/kg subcutaneously (SC), once a day (SID). Compared with control animals, prophylaxis or treatment with LMWH and GMI-1271 in a dose-dependent manner significantly decreased thrombosis. GMI-1271 significantly lowered tail bleeding times when compared to LMWH. GMI-1271 and LMWH prophylactically administered significantly decreased vein wall neutrophil cell extravasation. However, all treatment and prophylactic therapies significantly decreased vein wall monocyte extravasation versus controls. GMI-1271 prophylactic therapy significantly decreased intra-thrombus cell counts versus control animals and other treatment groups. Immunohistochemistry confirmed that both treatments with GMI-1271 and LMWH significantly decreased activated leukocyte migration. GMI-1271 therapy significantly decreased thrombus weight and resulted in significantly lower bleeding times than LMWH. GMI-1271 treated mice showed decreased local and systemic inflammatory effects while modulating neutrophil activation, suggesting that GMI-1271 is a viable therapeutic candidate for venous thrombosis prophylaxis and treatment.

Keywords

E-selectin inhibition - glycomimetic - venous thrombosis - animal models - inflammation
 

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