FXIII: mechanisms of action in the treatment of hemophilia A. (February 2014)

• Record Type: Journal Article
• Authors: Rea, C. J.; Foley, J. H.; Okaisabor, O.; Sørensen, B.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 12:Number 2(2014:Feb.)
• Page Start: 159
• Page End: 168
• Publication Date: 2014-02
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12478
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12478-abs-0001"> <title>Summary</title> <sec id="jth12478-sec-0001" sec-type="section"> <title>Background</title> <p>Hemophilia is characterized by abnormal thrombin generation and impaired clot stability. FXIII promotes clot stability and may be a useful adjunct treatment for hemophilia.</p> </sec> <sec id="jth12478-sec-0002" sec-type="section"> <title>Objectives</title> <p>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.</p> </sec> <sec id="jth12478-sec-0003" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="jth12478-sec-0004" sec-type="section"> <title>Results</title> <p>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<sup>−1</sup>, <italic>P</italic> < 0.05, <sc>anova</sc>). 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 (<italic>P</italic> < 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.</p> </sec> <sec id="jth12478-sec-0005" sec-type="section"> <title>Conclusion</title> <p>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.</p> </sec> </abstract>