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Targeting recombinant thrombomodulin fusion protein to red blood cells provides multifaceted thromboprophylaxis.

Authors
  • Zaitsev, Sergei
  • Kowalska, M Anna
  • Neyman, Michael
  • Carnemolla, Ronald
  • Tliba, Samira
  • Ding, Bi-Sen
  • Stonestrom, Aaron
  • Spitzer, Dirk
  • Atkinson, John P
  • Poncz, Mortimer
  • Cines, Douglas B
  • Esmon, Charles T
  • Muzykantov, Vladimir R
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
May 17, 2012
Volume
119
Issue
20
Pages
4779–4785
Identifiers
DOI: 10.1182/blood-2011-12-398149
PMID: 22493296
Source
Medline
License
Unknown

Abstract

Thrombin generates fibrin and activates platelets and endothelium, causing thrombosis and inflammation. Endothelial thrombomodulin (TM) changes thrombin's substrate specificity toward cleavage of plasma protein C into activated protein C (APC), which opposes its thrombotic and inflammatory activities. Endogenous TM activity is suppressed in pathologic conditions, and antithrombotic interventions involving soluble TM are limited by rapid blood clearance. To overcome this problem, we fused TM with a single chain fragment (scFv) of an antibody targeted to red blood cells. scFv/TM catalyzes thrombin-mediated generation of activated protein C and binds to circulating RBCs without apparent damage, thereby prolonging its circulation time and bioavailability orders of magnitude compared with soluble TM. In animal models, a single dose of scFv/TM, but not soluble TM, prevents platelet activation and vascular occlusion by clots. Thus, scFv/TM serves as a prodrug and provides thromboprophylaxis at low doses (0.15 mg/kg) via multifaceted mechanisms inhibiting platelets and coagulation.

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