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Hemophilia Animal Model Service

A central challenge in hemophilia animal model development lies in creating systems that accurately replicate the human coagulation system's complexity to ensure reliable translation of preclinical findings. Protheragen offers comprehensive animal model development services for hemophilia, providing researchers with genetically precise and pathologically faithful in vivo systems to accelerate therapeutic discovery and validation.

Overview of Hemophilia Animal Models

Hemophilia research relies on specialized animal models that replicate the human disease's coagulation deficiencies. These experimental systems are developed through targeted genetic modifications to disrupt specific clotting factor genes, primarily F8 for hemophilia A and F9 for hemophilia B. The resulting models demonstrate characteristic bleeding phenotypes that enable comprehensive evaluation of therapeutic candidates. Their applications span multiple research areas including pharmacokinetic studies of replacement therapies, efficacy assessment of novel bypassing agents, and long-term safety evaluation of gene-based treatments. These models serve as crucial platforms for understanding disease mechanisms, optimizing treatment regimens, and generating robust preclinical data required for regulatory approvals.

Animal models of hemophilia A and AAV treatment studies. Fig.1 Hemophilia A animal model and AAV treatment research. (Han J P, et al., 2023)

Our Services

At Protheragen, we are dedicated to advancing the research and therapeutic development for bleeding disorders by providing comprehensive and highly specialized animal model development services. Our expertise encompasses a wide range of coagulation deficiencies, including hemophilia A and B. We empower researchers with robust, validated, and customizable models that accurately recapitulate the complex pathophysiology of these disorders, thereby providing a critical foundation for clients' preclinical assessment of novel factor replacements, bypassing agents, and gene therapies.

Animal Models of Hemophilia

Model Name	Modeling Method	Sales Status	Detailed Description
F8-KO Mice	Knockout	Repository Live	F8-KO mice carry a knockout allele derived from the targeted deletion of exon 16-19.
F8-KO (2) Mice	Knockout	Embryo Cryopreservation	F8-KO (2) mice carry a knockout allele derived from the targeted deletion of exon 1-26.
F9-KO Mice	Knockout	Embryo Cryopreservation	The F9 gene is located on the X chromosome. In this F9 knockout mouse model, gRNAs were designed targeting exon 8 of F9 gene via gene editing technology. Loss of F9 caused coagulopathy in mice. Mice that are homozygous for F9 knockout are viable, fertile and normal in size. Normal fighting in the cage may cause bleeding or even death due to massive internal hemorrhaging. After the tail cutting, wounds must be cauterized to prevent homozygous knockout mice from blood loss and death. This strain is a powerful model for studying coagulopathy, gene therapy methods and function of factor IX mutations. F9-KO mice carry a knockout allele derived from the targeted deletion of exon 8.
F9-KO (2) Mice	Knockout	Repository Live	F9-KO (2) mice carry a knockout allele derived from the targeted deletion of exon 1-8.
B6-F8 KO Mice	Knockout	Normal Sales	The F8 gene encodes coagulation factor VIII (FVIII), a large plasma glycoprotein that plays a critical role in the intrinsic pathway of blood coagulation. Defects in the F8 gene cause hemophilia A (HA), an X-linked recessive bleeding disorder that predominantly affects males. Patients typically experience spontaneous or trauma-induced bleeding that fails to clot properly, with severe cases leading to disability from internal and joint hemorrhages, and potentially life-threatening complications. Clinically, exogenous FVIII replacement therapy effectively manages HA symptoms. Recent advances in gene therapy and genome editing technologies have brought new hope for HA treatment, with the potential to achieve long-term or permanent cure through repair or replacement of the defective F8 gene. The B6-F8 KO mouse model, constructed through gene-editing-mediated knockout of the murine ortholog of the human F8 gene, serves as a valuable research platform for studying hemophilia A.
Collagen/Factor VIII-Deficiency-Induced Hemophilia Model	Induced Method	Normal Sales	This model induces an acute bleeding phenotype by combining the inherent coagulation defect of Factor VIII deficiency with vascular injury triggered by the intravenous injection of collagen.

Case Study-F8I22I Mutant Mouse Model (Hemophilia A)

Model Introduction

Hemophilia A is an X-linked recessive bleeding disorder caused by mutations in the coagulation factor VIII (F8) gene. Among these, large inversions involving intron 22 represent one of the most frequent genetic lesions in severe cases. To faithfully model this human pathology, we generated the F8I22I mouse model using genome editing to reproduce the characteristic intron 22 inversion in the murine F8 gene. This model recapitulates the genetic etiology and severe bleeding phenotype observed in patients, providing a relevant tool for mechanistic and therapeutic studies.

Methodology

Animal Model: F8I22I homozygous mutant mice and wild-type (WT) controls on a C57BL/6 background were used. Adult male mice (12-16 weeks old) were utilized for subsequent phenotypic analyses.
Phenotypic Analysis Methods:
- Coagulation Profile: Plasma coagulation activity was assessed by measuring partial thromboplastin time (PT) and activated partial thromboplastin time (aPTT) to evaluate the extrinsic and intrinsic pathways, respectively.
- Hemostatic Capacity: An in vivo bleeding assay was performed to determine bleeding time, blood loss per body weight (Blood Loss/BW), and hemoglobin levels.

Phenotypic Analysis & Results

The F8I22I homozygous mice exhibited a severe hemophilia A phenotype:

Coagulation Defect: F8I22I mice displayed a characteristic coagulation abnormality, with a significantly prolonged activated partial thromboplastin time (aPTT) while partial thromboplastin time (PT) remained normal, confirming a specific impairment of the intrinsic coagulation pathway (Fig.2A).
Severe Bleeding Diathesis: In vivo bleeding assays showed that F8I22I mice exhibited severe hemophilia, characterized by prolonged bleeding time and significantly higher blood loss than WT mice. Since the in vivo bleeding assay was terminated at 20 minutes, the blood loss per unit body weight in F8I22I mice was more than four times that in WT mice. However, bleeding did not stop even at the end of the experiment (Fig.2B).

Phenotypic validation of the F8I22I hemophilia A mouse model.

Fig.2 Phenotypic characterization of the F8I22I mouse model of hemophilia A. (A) Coagulation activity was assessed by partial thromboplastin time (PT) and activated partial thromboplastin time (aPTT) (WT: n = 5, F8I22I: n=5). (B) In vivo bleeding analysis for confirmation of coagulation disorder (WT: n = 5, F8I22I: n = 5). Each dot represents data from an individual mouse and is presented as mean ± SEM. ns: not significant, ****p < 0.0001.

Conclusion

This case study validates the F8I22I mouse as a genetically accurate and phenotypically robust model for hemophilia A research. The model successfully recapitulates the key hallmarks of the disease, including a specific coagulation defect in the intrinsic pathway, severely impaired hemostasis, and deficient thrombin generation. This makes it an ideal preclinical tool for investigating hemophilia A pathophysiology and evaluating novel therapeutic strategies, such as gene therapy or hemostatic drugs.

Contact Us

Leveraging precise animal models, Protheragen is dedicated to providing a comprehensive suite of preclinical research services for hemophilia. Our services include pharmacodynamics (PD), pharmacokinetics (PK), and toxicology studies, all designed to support the development and regulatory approval of potential therapies. If you are interested in our animal model development services, please do not hesitate to contact us for more details and quotation information.

Reference

Han J P, Lee Y, Lee J H, et al. In vivo genome editing using 244-cis LNPs and low-dose AAV achieves therapeutic threshold in hemophilia A mice[J]. Molecular Therapy Nucleic Acids, 2023, 34.