RGD Reference Report - The severe spontaneous bleeding phenotype in a novel hemophilia A rat model is rescued by platelet FVIII expression. - Rat Genome Database

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The severe spontaneous bleeding phenotype in a novel hemophilia A rat model is rescued by platelet FVIII expression.

Authors: Shi, Qizhen  Mattson, Jeremy G  Fahs, Scot A  Geurts, Aron M  Weiler, Hartmut  Montgomery, Robert R 
Citation: Shi Q, etal., Blood Adv. 2020 Jan 14;4(1):55-65. doi: 10.1182/bloodadvances.2019000944.
RGD ID: 150520060
Pubmed: PMID:31899798   (View Abstract at PubMed)
PMCID: PMC6960468   (View Article at PubMed Central)
DOI: DOI:10.1182/bloodadvances.2019000944   (Journal Full-text)

Previous studies have shown that platelet-specific factor VIII (FVIII) expression (2bF8) restores hemostasis and induces immune tolerance in hemophilia A (HA) mice even with preexisting inhibitors. Here we investigated for the first time whether platelet FVIII expression can prevent severe spontaneous bleeding in rat HA, a model mimicking the frequent spontaneous bleeding in patients with severe HA. A novel FVIII-/- rat model in a Dahl inbred background (Dahl-FVIII-/-) with nearly the entire rat FVIII gene inverted was created by using a CRISPR/Cas9 strategy. There was no detectable FVIII in plasma. Spontaneous bleeding in the soft tissue, muscles, or joints occurred in 100% of FVIII-/- rats. Sixty-one percent developed anti-FVIII inhibitors after >=2 doses of recombinant human FVIII infusion. However, when 2bF8 transgene was crossed into the FVIII-/- background, none of the resulting 2bF8tg+FVIII-/- rats (with platelet FVIII levels of 28.26 ± 7.69 mU/108 platelets and undetectable plasma FVIII) ever had spontaneous bleeding. When 2bF8tg bone marrow (BM) was transplanted into FVIII-/- rats, only 1 of 7 recipients had a bruise at the early stage of BM reconstitution, but no other spontaneous bleeding was observed during the study period. To confirm that the bleeding diathesis in FVIII-/- rats was ameliorated after platelet FVIII expression, rotational thromboelastometry and whole-blood thrombin generation assay were performed. All parameters in 2bF8tg BM transplantation recipients were significantly improved compared with FVIII-/- control rats. Of note, neither detectable levels of plasma FVIII nor anti-FVIII inhibitors were detected in 2bF8tg BM transplantation recipients. Thus, platelet-specific FVIII expression can efficiently prevent severe spontaneous bleeding in FVIII-/- rats with no anti-FVIII antibody development.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F8Ratfactor VIII deficiency treatmentIMP  RGD 
F8Humanfactor VIII deficiency treatmentISOF8 (Rattus norvegicus) RGD 
F8Mousefactor VIII deficiency treatmentISOF8 (Rattus norvegicus) RGD 
F8em1SageRatfactor VIII deficiency treatmentIMP  RGD 
F8em1McwiRatfactor VIII deficiency treatmentIMP  RGD 
SD-F8em1Sage-/-/NovoRatfactor VIII deficiency treatmentIMP  RGD 
SS-F8em1McwiRatfactor VIII deficiency treatmentIMP  RGD 
F8Rathemarthrosis treatmentIMP  RGD 
F8Humanhemarthrosis treatmentISOF8 (Rattus norvegicus) RGD 
F8Mousehemarthrosis treatmentISOF8 (Rattus norvegicus) RGD 
F8em1SageRathemarthrosis treatmentIMP  RGD 
F8em1McwiRathemarthrosis treatmentIMP  RGD 
SD-F8em1Sage-/-/NovoRathemarthrosis treatmentIMP  RGD 
SS-F8em1McwiRathemarthrosis treatmentIMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F8Ratabnormal hemostasis treatmentIMP  RGD 
F8em1SageRatabnormal hemostasis treatmentIMP  RGD 
F8em1McwiRatabnormal hemostasis treatmentIMP  RGD 
SD-F8em1Sage-/-/NovoRatabnormal hemostasis treatmentIMP  RGD 
SS-F8em1McwiRatabnormal hemostasis treatmentIMP  RGD 
F8Rathemarthrosis treatmentIMP  RGD 
F8em1SageRathemarthrosis treatmentIMP  RGD 
F8em1McwiRathemarthrosis treatmentIMP  RGD 
SD-F8em1Sage-/-/NovoRathemarthrosis treatmentIMP  RGD 
SS-F8em1McwiRathemarthrosis treatmentIMP  RGD 
F8Ratincreased bleeding time treatmentIMP  RGD 
F8em1SageRatincreased bleeding time treatmentIMP  RGD 
F8em1McwiRatincreased bleeding time treatmentIMP  RGD 
SD-F8em1Sage-/-/NovoRatincreased bleeding time treatmentIMP  RGD 
SS-F8em1McwiRatincreased bleeding time treatmentIMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
F8  (coagulation factor VIII)
F8em1Sage  (coagulation factor VIII, procoagulant component; zinc finger nuclease induced mutant1, Sage)
F8em1Mcwi  (coagulation factor VIII, procoagulant component; CRISPR/Cas9 induced mutant1, Mcwi)

Genes (Mus musculus)
F8  (coagulation factor VIII)

Genes (Homo sapiens)
F8  (coagulation factor VIII)


Additional Information