Targeting recombinant thrombomodulin fusion protein to red blood cells provides multifaceted thromboprophylaxis. Academic Article Article uri icon

Overview

MeSH

  • Animals
  • Cells, Cultured
  • Drosophila
  • Humans
  • Mice
  • Models, Biological
  • Molecular Targeted Therapy
  • Protein Binding
  • Protein C
  • Recombinant Fusion Proteins
  • Single-Chain Antibodies

MeSH Major

  • Chemoprevention
  • Drug Delivery Systems
  • Erythrocytes
  • Thrombomodulin
  • Thrombosis

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.

publication date

  • May 17, 2012

has subject area

  • Animals
  • Cells, Cultured
  • Chemoprevention
  • Drosophila
  • Drug Delivery Systems
  • Erythrocytes
  • Humans
  • Mice
  • Models, Biological
  • Molecular Targeted Therapy
  • Protein Binding
  • Protein C
  • Recombinant Fusion Proteins
  • Single-Chain Antibodies
  • Thrombomodulin
  • Thrombosis

Research

keywords

  • Evaluation Studies
  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3367878

Digital Object Identifier (DOI)

  • 10.1182/blood-2011-12-398149

PubMed ID

  • 22493296

Additional Document Info

start page

  • 4779

end page

  • 4785

volume

  • 119

number

  • 20