RGD Reference Report - Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice. - Rat Genome Database

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Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice.

Authors: Arumugam, PI  Mullins, ES  Shanmukhappa, SK  Monia, BP  Loberg, A  Shaw, MA  Rizvi, T  Wansapura, J  Degen, JL  Malik, P 
Citation: Arumugam PI, etal., Blood. 2015 Oct 8;126(15):1844-55. doi: 10.1182/blood-2015-01-625707. Epub 2015 Aug 18.
RGD ID: 11565074
Pubmed: PMID:26286849   (View Abstract at PubMed)
PMCID: PMC4600020   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2015-01-625707   (Journal Full-text)

Sickle cell disease (SCD) results in vascular occlusions, chronic hemolytic anemia, and cumulative organ damage. A conspicuous feature of SCD is chronic inflammation and coagulation system activation. Thrombin (factor IIa [FIIa]) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin (factor II [FII]) levels in SCD will limit vaso-occlusion, vasculopathy, and inflammation, we used 2 strategies to suppress FII in SCD mice. Weekly administration of FII antisense oligonucleotide "gapmer" to Berkeley SCD mice to selectively reduce circulating FII levels to approximately 10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done using mice with genetic diminution of circulating FII. Here, cohorts of FII(lox/-) mice (constitutively carrying approximately 10% normal FII) and FII(WT) mice were tracked in parallel for a year following the imposition of SCD via hematopoietic stem cell transplantation. This genetically imposed suppression of FII levels resulted in an impressive reduction in inflammation (reduction in leukocytosis, thrombocytosis, and circulating interleukin-6 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating soluble vascular cell adhesion molecule), and a significant improvement in SCD-associated end-organ damage (nephropathy, pulmonary hypertension, pulmonary inflammation, liver function, inflammatory infiltration, and microinfarctions). Notably, all of these benefits were achieved with a relatively modest 1.25-fold increase in prothrombin times, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
sickle cell anemia disease_progressionISOF2 (Mus musculus)11565074; 11565074 RGD 
sickle cell anemia disease_progressionIMP 11565074 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