Murine Models of Hemostasis: How to Assess Bleeding in Mice and Clinical Relevance of These Models for Testing New Therapeutics.

CLINICAL PROBLEM: Congenital bleeding disorders stem from genetic defects affecting procoagulant proteins (such as von Willebrand Factor, factor VIII, or factor IX) or platelet proteins (such as integrin αIIbβ3 or glycoprotein Ibα). Despite advances in our knowledge of the hemostatic system, there are still gaps in our understanding of the interplay between the various hemostatic actors, limiting the development of efficient therapeutic agents for each of these disorders.

RECOMMENDATIONS: Mouse models have a proven record in their use as preclinical tools for the development and testing of therapeutics for bleeding disorders, with several bleeding models being available. However, a lack of standardization for most of these models complicates inter-laboratory comparisons. It is recommended, therefore, that experimental variables are standardized as much as possible to ensure reproducible results, including parameters like temperature and anesthesia. Also, the balance between the use of male and female mice should be considered.

SUMMARY OF STRENGTHS AND WEAKNESSES OF MOUSE MODELS OF BLEEDING: Murine hemostasis is relatively similar to human hemostasis, representing a clear strength in translation to the clinic. Among available bleeding models, the tail clip assay is popular for its simplicity, although its standardization might be improved. Other techniques, such as the saphenous vein and laser-induced bleeding models, offer high reproducibility and real-time visualization but require advanced surgical or technological skills. A primary weakness is that most knockout mice do not exhibit the spontaneous hemorrhagic events or joint damage characteristic of human patients. Additionally, species-specific differences can occasionally hamper the testing of therapeutic candidates.