Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

Dongying Ma, Daniella M. Mizurini, Teresa C.F. Assumpção, Yuan Li, Yanwei Qi, Michail Kotsyfakis, José M.C. Ribeiro, Robson Q. Monteiro, Ivo M.B. Francischetti

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

The identity of vampire bat saliva anticoagulant remained elusive for almost a century. Sequencing the salivary gland genes from the vampire bat Desmodus rotundus identified Desmolaris as a novel 21.5-kDa naturally deleted (Kunitz 1-domainless) form of tissue factor pathway inhibitor. Recombinant Desmolaris was expressed in HEK293 cells and characterizedas a slow, tight, andnoncompetitive inhibitor of factor (F) XIa byamechanism modulated by heparin. Desmolaris also inhibits FXa with lower affinity, independently of protein S. In addition, Desmolaris binds kallikrein and reduces bradykinin generation in plasma activated with kaolin. Truncated and mutated forms of Desmolaris determined that Arg32 in the Kunitz-1 domain is critical for protease inhibition. Moreover, Kunitz-2 and the carboxyl-terminus domains mediate interaction of Desmolaris with heparin and are required for optimal inhibition of FXIa and FXa. Notably, Desmolaris (100 μg/kg) inhibited FeCl3-induced carotid artery thrombus without impairing hemostasis. These results imply that FXIa is the primary in vivo target for Desmolaris at antithrombotic concentrations. Desmolaris also reduces the polyphosphateinduced increase in vascular permeability and collagen- and epinephrine-mediated thromboembolism inmice. Desmolaris emerges as a novel anticoagulant targeting FXIa under conditions in which the coagulation activation, particularly the contact pathway, plays a major pathological role.

Original languageEnglish (US)
Pages (from-to)4094-4106
Number of pages13
JournalBlood
Volume122
Issue number25
DOIs
StatePublished - 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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