The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A

Matthew J Flick; Anil K Chauhan; Malinda Frederick; Kathryn E Talmage; Keith W Kombrinck; Whitney Miller; Eric S Mullins; Joseph S Palumbo; Xunzhen Zheng; Naomi L Esmon; Charles T Esmon; Sherry Thornton; Ann Becker; Leslie A Pelc; Enrico Di Cera; Denisa D Wagner; Jay L Degen

doi:10.1182/blood-2010-08-304915

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The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A

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The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A

Matthew J Flick, Anil K Chauhan, Malinda Frederick, Kathryn E Talmage, Keith W Kombrinck, Whitney Miller, Eric S Mullins, Joseph S Palumbo, Xunzhen Zheng, Naomi L Esmon, …

Blood, Vol.117(23), pp.6326-6337

06/09/2011

DOI: 10.1182/blood-2010-08-304915

PMCID: PMC3122951

PMID: 21436072

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Abstract

Thrombin is a positive mediator of thrombus formation through the proteolytic activation of protease-activated receptors (PARs), fibrinogen, factor XI (fXI), and other substrates, and a negative regulator through activation of protein C, a natural anticoagulant with anti-inflammatory/cytoprotective properties. Protease-engineering studies have established that 2 active-site substitutions, W215A and E217A (fII WE ), result in dramatically reduced catalytic efficiency with procoagulant substrates while largely preserving thrombomodulin (TM)–dependent protein C activation. To explore the hypothesis that a prothrombin variant favoring antithrombotic pathways would be compatible with development but limit inflammatory processes in vivo, we generated mice carrying the fII WE mutations within the endogenous prothrombin gene. Unlike fII-null embryos, fII WE/WE mice uniformly developed to term. Nevertheless, these mice ultimately succumbed to spontaneous bleeding events shortly after birth. Heterozygous fII WT/WE mice were viable and fertile despite a shift toward an antithrombotic phenotype exemplified by prolonged tail-bleeding times and times-to-occlusion after FeCl 3 vessel injury. More interestingly, prothrombin WE expression significantly ameliorated the development of inflammatory joint disease in mice challenged with collagen-induced arthritis (CIA). The administration of active recombinant thrombin WE also suppressed the development of CIA in wild-type mice. These studies provide a proof-of-principle that pro/thrombin variants engineered with altered substrate specificity may offer therapeutic opportunities for limiting inflammatory disease processes.

Thrombosis and Hemostasis

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Title: Subtitle: The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A
Creators: Matthew J Flick - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Anil K Chauhan - Immune Disease Institute and Department of Pathology, Harvard Medical School, Boston, MA
Malinda Frederick - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Kathryn E Talmage - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Keith W Kombrinck - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Whitney Miller - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Eric S Mullins - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Joseph S Palumbo - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Xunzhen Zheng - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Naomi L Esmon - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Charles T Esmon - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Sherry Thornton - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Ann Becker - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Leslie A Pelc - Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO
Enrico Di Cera - Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO
Denisa D Wagner - Immune Disease Institute and Department of Pathology, Harvard Medical School, Boston, MA
Jay L Degen - Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Resource Type: Journal article
Publication Details: Blood, Vol.117(23), pp.6326-6337
Publisher: American Society of Hematology
DOI: 10.1182/blood-2010-08-304915
PMID: 21436072
PMCID: PMC3122951
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: R01 AR056990; R01 HL085357; R01 HL096126; R01 HL041002; R01 HL049413; R01 HL058141; R01 HL073813; R44 HL095315 / National Institutes of Health
Language: English
Date published: 06/09/2011
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094609702771

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