Termination of bleeding by a specific, anticatalytic antibody against plasmin

Tieqiang Zhao, Aiilyan Houng, Guy L. Reed

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Excessive, plasmin-mediated fibrinolysis augments bleeding and contributes to death in some patients. Current therapies for fibrinolytic bleeding are limited by modest efficacy, low potency, and off-target effects. Objectives: To determine whether an antibody directed against unique loop structures of the plasmin protease domain may have enhanced specificity and potency for blocking plasmin activity, fibrinolysis, and experimental hemorrhage. Methods: The binding specificity, affinity, protease cross-reactivity and antifibrinolytic properties of a monoclonal plasmin inhibitor antibody (Pi) were examined and compared with those of epsilon aminocaproic acid (EACA), which is a clinically used fibrinolysis inhibitor. Results: Pi specifically recognized loop 5 of the protease domain, and did not bind to other serine proteases or nine other non-primate plasminogens. Pi was ~7 logs more potent in neutralizing plasmin cleavage of small-molecule substrates and >3 logs more potent in quenching fibrinolysis than EACA. Pi was similarly effective in blocking catalysis of a small-molecule substrate as α2-antiplasmin, which is the most potent covalent inhibitor of plasmin, and was a more potent fibrinolysis inhibitor. Fab or chimerized Fab fragments of Pi were equivalently effective. In vivo, in a humanized model of fibrinolytic surgical bleeding, Pi significantly reduced bleeding to a greater extent than a clinical dose of EACA. Conclusions: A mAb directed against unique loop sequences in the protease domain is a highly specific, potent, competitive plasmin inhibitor that significantly reduces experimental surgical bleeding in vivo.

Original languageEnglish (US)
Pages (from-to)1461-1469
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2019

Keywords

  • antifibrinolytic agents
  • fibrinolysis
  • hemorrhage
  • plasmin
  • α-antiplasmin

ASJC Scopus subject areas

  • Hematology

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