Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis
Donny Hanjaya-Putra, … , Karlheinz Peter, Elliot L. Chaikof
Donny Hanjaya-Putra, … , Karlheinz Peter, Elliot L. Chaikof
Published August 9, 2018
Citation Information: JCI Insight. 2018;3(15):e99329. https://doi.org/10.1172/jci.insight.99329.
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Research Article Cardiology Hematology

Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis

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

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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Figure 4

SCE5-TAP inhibits deep venous thrombosis without increased bleeding risk.

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SCE5-TAP inhibits deep venous thrombosis without increased bleeding risk...
An electrolytic IVC model (EIM) was used to generate a nonocclusive venous thrombus in the IVC. SCE5-TAP (0.5 μg/g s.c.), LMWH (4 μg/g s.c.), or Rivaroxaban (1 μg/g per os) were administered 4 hours prior to electrolytic injury and 24 hours after injury. The IVC was harvested at 48 hours for thrombus characterization. (A and B) A uniform length of IVC was harvested and immediately weighed to determine vessel wall and thrombus weight. Control enrollment included uninjured IVC without thrombus induction; n = 10–35 mice/group. Data represent mean ± SD, ***P ≤ 0.001 vs. saline control. (C and D) Thrombus area was characterized from H&E-stained sections. Thrombus area is reported as area (mm2)/aortic wall thickness (mm); n = 5 mice/group, 3 sections/mouse. Data represent mean ± SD, **P ≤ 0.01 vs. saline control. Scale bars: 500 μm. (E–G) Systemic bleeding risk was characterized 4 hours after administration of test compound by measuring circulating anti-FXa activity (E), tail transection bleeding time (F), and tail transection blood loss (G); n = 5–10 mice/group. Data represent mean ± SD, **P ≤ 0.01 and ***P ≤ 0.001. All P values were determined by ANOVA and Bonferroni’s multiple comparison test.