TY - JOUR
T1 - Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo
AU - Ma, Dongying
AU - Mizurini, Daniella M.
AU - Assumpção, Teresa C.F.
AU - Li, Yuan
AU - Qi, Yanwei
AU - Kotsyfakis, Michail
AU - Ribeiro, José M.C.
AU - Monteiro, Robson Q.
AU - Francischetti, Ivo M.B.
N1 - Publisher Copyright:
Copyright © 2011 by The American Society of Hematology; all rights reserved.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2013-08-517474
DO - 10.1182/blood-2013-08-517474
M3 - Article
C2 - 24159172
AN - SCOPUS:84893437698
SN - 0006-4971
VL - 122
SP - 4094
EP - 4106
JO - Blood
JF - Blood
IS - 25
ER -