ADAMTS13 exerts a thrombolytic effect in microcirculation.
Recombinant tissue plasminogen activator (r-tPA) is the drug of choice for thrombolysis, but it is associated with a significant risk of bleeding and is not always successful. By cleaving von Willebrand factor (VWF), the metalloprotease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) down-regulates thrombus formation in injured vessels. We investigated whether recombinant ADAMTS13 (r-ADAMTS13) induces thrombolysis in vivo in mice. Thrombosis was produced by ferric chloride-induced (FeCl(3)) injury in the venules of a dorsal skinfold chamber. Phosphate-buffered saline (PBS, vehicle), r-tPA or r-ADAMTS13, supplemented with hirudin (to stop on-going thrombin generation), was directly applied onto the occluded vessel, and thrombus dissolution was evaluated by intravital microscopy. The incidence of blood flow restoration significantly increased 30 minutes (min) after r-ADAMTS13 vs. PBS treatment (60% vs. 0%, p<0.05) and 60 min after r-tPA treatment (75% vs. 17%, p<0.05). Both r-tPA and r-ADAMTS13 significantly reduced thrombus size 60 min after their superfusion (53.2% and 62.3% of the initial thrombus size, p<0.05 and p<0.01, respectively). Bleeding occurred in all r-tPA-treated chambers, while it was absent in mice treated with r-ADAMTS13 or PBS. We observed that, similar to r-tPA, r-ADAMTS13 can dissolve occlusive thrombi induced by FeCl(3) injury in venules. In contrast to r-tPA, the in vivo thrombolytic effect of ADAMTS13 was not associated with any signs of haemorrhage. ADAMTS13 could represent a new therapeutic option for thrombolysis.
Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
Marilena
M
Crescente
Grace M
GM
Thomas
Melanie
M
Demers
Jaymie R
JR
Voorhees
Siu Ling
SL
Wong
Benoit
B
Ho-Tin-Noé
Denisa D
DD
Wagner
D051722:ADAM Proteins / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000071120:ADAMTS13 Protein; D000818:Animals; D002712:Chlorides / Q000633:toxicity; D003199:Computer Systems; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005290:Ferric Compounds / Q000633:toxicity; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D008853:Microscopy / Q000379:methods; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D012884:Skin Window Technique; D015912:Thrombolytic Therapy / Q000009:adverse effects; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use; D020246:Venous Thrombosis / Q000139:chemically induced / Q000188:drug therapy*; D014699:Venules
D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; C024555:ferric chloride