P-selectin inhibition therapeutically promotes thrombus resolution and prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor.

Abstract

OBJECTIVE:

Aptamers are oligonucleotides targeting protein-protein interactions with pharmacokinetic profiles and activity reversal options. Although P-selectin and von Willebrand factor (vWF) have been implicated in the development of venous thrombosis (VT), no studies have directly compared aptamer efficacy with standard of care in VT. In this study, ARC5692, an anti-P-selectin aptamer, and ARC15105, an anti-vWF aptamer, were compared with low-molecular-weight heparin, enoxaparin, to test the efficacy of P-selectin or vWF inhibition in promoting thrombus resolution and preventing vein wall fibrosis, in a baboon model of VT.

APPROACH AND RESULTS:

Groups were as follows: treatment arm: animals received P-selectin or vWF aptamer inhibitors or enoxaparin (n=3 per group). Controls received no treatment (n=3). Prophylactic arm: animals received P-selectin inhibitor (n=4) or vWF inhibitor (n=3). Treatment arm: P-selectin-inhibitor demonstrated a significant improvement in vein recanalization by magnetic resonance venography (73% at day 21), and significantly decreased vein wall collagen, compared with all groups. Anti-P-selectin equaled enoxaparin in maintaining valve competency by ultrasound. All control animals had compromised valve competency post thrombosis. Prophylactic arm: animals receiving P-selectin and vWF inhibitors demonstrated improved vein recanalization by magnetic resonance venography versus controls (80% and 85%, respectively, at day 21). Anti-P-selectin protected iliac valve function better than anti-vWF, and both improved valve function versus controls. No adverse bleeding events were observed.

CONCLUSIONS:

The P-selectin inhibitor aptamer promoted iliac vein recanalization, preserved valve competency, and decreased vein wall fibrosis. The results of this work suggest that P-selectin inhibition maybe an ideal target in the treatment and prophylaxis of deep VT, warranting clinical trials.

• Authors: Jose A Diaz, Shirley K Wrobleski, Christine M Alvarado, Angela E Hawley, Nichole K Doornbos, Patrick A Lester, Suzan E Lowe, Joy E Gabriel, Karen J Roelofs, Peter K Henke, Robert G Schaub, Thomas W Wakefield, Daniel D Myers Jr
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 4 Pg. 829-37 (Apr 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 25657307 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• ARC15105
• ARC5692
• Aptamers, Nucleotide
• Enoxaparin
• Fibrinolytic Agents
• P-Selectin
• von Willebrand Factor
• Fibrin
• Collagen

Topics

• Animals
• Aptamers, Nucleotide (pharmacology)
• Blood Coagulation (drug effects)
• Collagen (metabolism)
• Disease Models, Animal
• Enoxaparin (pharmacology)
• Fibrin (metabolism)
• Fibrinolytic Agents (pharmacology)
• Fibrosis
• Iliac Vein (diagnostic imaging, drug effects, metabolism, pathology)
• Leukocytes (drug effects, metabolism)
• Magnetic Resonance Angiography
• P-Selectin (antagonists & inhibitors, metabolism)
• Papio
• Phlebography (methods)
• Platelet Aggregation (drug effects)
• Time Factors
• Ultrasonography
• Venous Thrombosis (diagnostic imaging, metabolism, pathology, prevention & control)
• Venous Valves (drug effects, metabolism, pathology)
• von Willebrand Factor (antagonists & inhibitors, metabolism)