RGD Reference Report - The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A. - Rat Genome Database

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

Authors: Flick, MJ  Chauhan, AK  Frederick, M  Talmage, KE  Kombrinck, KW  Miller, W  Mullins, ES  Palumbo, JS  Zheng, X  Esmon, NL  Esmon, CT  Thornton, S  Becker, A  Pelc, LA  Di Cera, E  Wagner, DD  Degen, JL 
Citation: Flick MJ, etal., Blood. 2011 Jun 9;117(23):6326-37. Epub 2011 Mar 24.
RGD ID: 5147764
Pubmed: PMID:21436072   (View Abstract at PubMed)
PMCID: PMC3122951   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2010-08-304915   (Journal Full-text)

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 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Arthritis  ISOF2 (Mus musculus)5147764; 5147764 RGD 
Experimental Arthritis  IMP 5147764 RGD 

Objects Annotated

Genes (Rattus norvegicus)
F2  (coagulation factor II, thrombin)

Genes (Mus musculus)
F2  (coagulation factor II)

Genes (Homo sapiens)
F2  (coagulation factor II, thrombin)


Additional Information