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

Sergei Zaitsev, M. Anna Kowalska, Michael Neyman, Ronald Carnemolla, Samira Tliba, Bi Sen Ding, Aaron Stonestrom, Dirk Spitzer, John P. Atkinson, Mortimer Poncz, Douglas B. Cines, Charles T. Esmon, Vladimir R. Muzykantov

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish
Pages (from-to)4779-4785
Number of pages7
JournalBlood
Volume119
Issue number20
DOIs
StatePublished - May 17 2012

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