title: Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo.
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 characterized as a slow, tight, and noncompetitive inhibitor of factor (F) XIa by a mechanism 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 polyphosphate-induced increase in vascular permeability and collagen- and epinephrine-mediated thromboembolism in mice. Desmolaris emerges as a novel anticoagulant targeting FXIa under conditions in which the coagulation activation, particularly the contact pathway, plays a major pathological role.
authors.affiliation: Vector Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Dongying
authors.initials: D
authors.lastname: Ma
authors.forename: Daniella M
authors.initials: DM
authors.lastname: Mizurini
authors.forename: Teresa C F
authors.initials: TC
authors.lastname: Assumpção
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Qi
authors.forename: Michail
authors.initials: M
authors.lastname: Kotsyfakis
authors.forename: José M C
authors.initials: JM
authors.lastname: Ribeiro
authors.forename: Robson Q
authors.initials: RQ
authors.lastname: Monteiro
authors.forename: Ivo M B
authors.initials: IM
authors.lastname: Francischetti
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D001920:Bradykinin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002685:Chiroptera; D002712:Chlorides / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D015951:Factor Xa / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005290:Ferric Compounds / Q000009:adverse effects / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007610:Kallikreins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009676:Noxae / Q000009:adverse effects / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012471:Salivary Proteins and Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D002712:Chlorides; D065427:Factor Xa Inhibitors; D005290:Ferric Compounds; D009676:Noxae; D012471:Salivary Proteins and Peptides; C586269:desmolaris protein, Desmodus rotundus; D007610:Kallikreins; D015951:Factor Xa; D001920:Bradykinin; C024555:ferric chloride