Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis Academic Article uri icon

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.

authors

  • Hanjaya-Putra, D
  • Haller, C
  • Wang, X
  • Dai, E
  • Lim, B
  • Liu, L
  • Jaminet, P
  • Yao, J
  • Searle, A
  • Bonnard, T
  • Hagemeyer, CE
  • Peter, Karlheinz
  • Chaikof, EL

publication date

  • 2018