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.

Disease Annotations    
factor VIII deficiency  (IMP,ISO)
hemarthrosis  (IMP,ISO)

Phenotype Annotations    

Mammalian Phenotype
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