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

Research output: Contribution to journalArticleResearchpeer-review

6 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., ... 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
Hanjaya-Putra, Donny ; Haller, Carolyn ; Wang, Xiaowei ; Dai, Erbin ; Lim, Bock ; Liu, Liying ; Jaminet, Patrick ; Yao, Joy ; Searle, Amy ; Bonnard, Thomas ; Hagemeyer, Christoph E. ; Peter, Karlheinz ; Chaikof, Elliot L. / Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis. In: JCI Insight. 2018 ; Vol. 3, No. 15. pp. 1-18.
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Hanjaya-Putra, D, Haller, C, Wang, X, Dai, E, Lim, B, Liu, L, Jaminet, P, Yao, J, Searle, A, Bonnard, T, Hagemeyer, CE, Peter, K & Chaikof, EL 2018, 'Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis', JCI Insight, vol. 3, no. 15, pp. 1-18. https://doi.org/10.1172/jci.insight.99329

Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis. / Hanjaya-Putra, Donny; Haller, Carolyn; Wang, Xiaowei; Dai, Erbin; Lim, Bock; Liu, Liying; Jaminet, Patrick; Yao, Joy; Searle, Amy; Bonnard, Thomas; Hagemeyer, Christoph E.; Peter, Karlheinz; Chaikof, Elliot L.

In: JCI Insight, Vol. 3, No. 15, 09.08.2018, p. 1-18.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis

AU - Hanjaya-Putra, Donny

AU - Haller, Carolyn

AU - Wang, Xiaowei

AU - Dai, Erbin

AU - Lim, Bock

AU - Liu, Liying

AU - Jaminet, Patrick

AU - Yao, Joy

AU - Searle, Amy

AU - Bonnard, Thomas

AU - Hagemeyer, Christoph E.

AU - Peter, Karlheinz

AU - Chaikof, Elliot L.

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N2 - 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.

AB - 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.

KW - Cardiology

KW - Hematology

KW - Pharmacology

KW - Platelets

KW - Thrombosis

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U2 - 10.1172/jci.insight.99329

DO - 10.1172/jci.insight.99329

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JO - JCI Insight

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SN - 2379-3708

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