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J Thromb Haemost. 2014 Feb;12(2):159-68. doi: 10.1111/jth.12478.

FXIII: mechanisms of action in the treatment of hemophilia A.

Author information

1
King's College London School of Medicine, London, UK.

Abstract

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.

KEYWORDS:

FXIII (28-41); blood coagulation; hemophilia A; hemostasis; therapeutics

PMID:
24354581
DOI:
10.1111/jth.12478
[Indexed for MEDLINE]
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