Parts of this work were presented at the 2010 National Hemophilia Foundation Meeting in New Orleans.
ORIGINAL ARTICLE Clinical haemophilia
The influence of prophylactic factor VIII in severe haemophilia A
Article first published online: 7 SEP 2011
© 2011 Blackwell Publishing Ltd
Volume 18, Issue 2, pages 193–199, March 2012
How to Cite
GISSEL, M., WHELIHAN, M. F., FERRIS, L. A., MANN, K. G., RIVARD, G. E. and BRUMMEL-ZIEDINS, K. E. (2012), The influence of prophylactic factor VIII in severe haemophilia A. Haemophilia, 18: 193–199. doi: 10.1111/j.1365-2516.2011.02638.x
- Issue published online: 16 FEB 2012
- Article first published online: 7 SEP 2011
- Accepted after revision 26 July 2011
- factor VIII;
- factor XIII;
- inhibitory antibody;
- thrombin generation
Summary. Haemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Our objective was to evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)-initiated blood coagulation in severe haemophilia utilizing both empirical and computational models. We investigated twenty-five clinically severe haemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact-pathway inhibited whole blood ± an anti-fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. As a result of prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from <1% to 22%. Thrombin generation (maximum level and rate) in both empirical and computational systems increased as the level of fVIII increased. FXIII activation rates also increased as the fVIII level increased. Upon suppression of fVIII, thrombin generation became comparable in both systems. Plasma composition analysis showed a negative correlation between bleeding history and computational thrombin generation in the absence of fVIII. Residual prophylactic fVIII directly causes an increase in thrombin generation and fibrin cross-linking in individuals with clinically severe haemophilia A. The combination of each individual’s coagulation factors (outside of fVIII) determine each individual’s baseline thrombin potential and may affect bleeding risk.