Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis

Donny Hanjaya-Putra, Carolyn Haller, Xiaowei Wang, Erbin Dai, Bock Lim, Liying Liu, Patrick Jaminet, Joy Yao, Amy Searle, Thomas Bonnard, Christoph E. Hagemeyer, Karlheinz Peter, Elliot L. Chaikof

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8 Citations (Scopus)

Abstract

Despite advances in antithrombotic therapy, the risk of recurrent coronary/cerebrovascular ischemia or venous thromboembolism remains high. Dual pathway antithrombotic blockade, using both antiplatelet and anticoagulant therapy, offers the promise of improved thrombotic protection; however, widespread adoption remains tempered by substantial risk of major bleeding. Here, we report a dual pathway therapeutic capable of site-specific targeting to activated platelets and therapeutic enrichment at the site of thrombus growth to allow reduced dosing without compromised antithrombotic efficacy. We engineered a recombinant fusion protein, SCE5-TAP, which consists of a single-chain antibody (SCE5) that targets and blocks the activated GPIIb/IIIa complex, and tick anticoagulant peptide (TAP), a potent direct inhibitor of activated factor X (FXa). SCE5-TAP demonstrated selective platelet targeting and inhibition of thrombosis in murine models of both carotid artery and inferior vena cava thrombosis, without a significant impact on hemostasis. Selective targeting to activated platelets provides an attractive strategy to achieve high antithrombotic efficacy with reduced risk of bleeding complications.

Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalJCI Insight
Volume3
Issue number15
DOIs
Publication statusPublished - 9 Aug 2018

Keywords

  • Cardiology
  • Hematology
  • Pharmacology
  • Platelets
  • Thrombosis

Cite this

Hanjaya-Putra, D., Haller, C., Wang, X., Dai, E., Lim, B., Liu, L., Jaminet, P., Yao, J., Searle, A., Bonnard, T., Hagemeyer, C. E., Peter, K., & Chaikof, E. L. (2018). Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis. JCI Insight, 3(15), 1-18. https://doi.org/10.1172/jci.insight.99329