FXIII: mechanisms of action in the treatment of hemophilia A

Background: Hemophilia is characterized by abnormal thrombin generation and impaired clot stability. FXIII promotes clot stability and may be a useful adjunct treatment for hemophilia.

Objectives: This study examined the clot stabilizing effects and safety of supra-physiological FXIII and explored the mechanisms via which FXIII exerts its effects in hemophilia A.

Methods: The effects of FXIII on clot formation and stability were examined using a thromboelastometry assay and blood samples collected from six patients with severe hemophilia A. The effect of FXIII on clot formation was also assessed using a murine model. The mechanisms of FXIII action in hemophilia A were explored by measuring thrombin generation, rates of FXIII activation and effects on clot permeability, pore size and fibrin fiber diameter.

Results: This study demonstrates that supra-physiological concentrations of FXIII stabilize clots in blood from patients with hemophilia by improving resistance to t-Pa-induced fibrinolysis even at low concentrations of FVIII (FVIII< 0.1 IU mL⁻¹, P < 0.05, anova). Addition of FXIII stoichiometrically up-regulates its activation, correcting the fibrin clot structure, reducing clot permeability and facilitating thrombin generation; FXIII significantly shortens ttPeak and lagtime (P < 0.05) in FVIII-deficient plasma, providing a novel explanation for its positive effects on clot stability and structure. The murine model indicates that supra-physiological FXIII is tolerated and does not significantly alter time to clot formation.

Conclusion: The effects of FXIII on clot stability and physical clot structure are seen at low concentrations of FVIII, indicating that FXIII could be a useful treatment in a variety of clinical scenarios.