The dimeric FXIII-A
2
, a pro-transglutaminase is the catalytic part of the heterotetrameric coagulation FXIII-A
2
B
2
complex that upon activation by calcium binding/thrombin cleavage covalently cross-links preformed fibrin clots protecting them from premature fibrinolysis. Our study characterizes the recently disclosed three calcium binding sites of FXIII-A concerning evolution, mutual crosstalk, thermodynamic activation profile, substrate binding, and interaction with other similarly charged ions. We demonstrate unique structural aspects within FXIII-A calcium binding sites that give rise to functional differences making FXIII unique from other transglutaminases. The first calcium binding site showed an antagonistic relationship towards the other two. The thermodynamic profile of calcium/thrombin-induced FXIII-A activation explains the role of bulk solvent in transitioning its zymogenic dimeric form to an activated monomeric form. We also explain the indirect effect of solvent ion concentration on FXIII-A activation. Our study suggests FXIII-A calcium binding sites could be putative pharmacologically targetable regions.
The study evaluated the quality of plasma obtained after whole-blood filtration with four different polyester filters and one polyurethane filter. The activities of coagulation factors and proteinase inhibitors were not or only negligibly affected by filtration, in all experiments. Filtration did not increase markers of clotting and fibrinolysis. Only a strong neutrophil and complement activation was observed, which depended on the type of filter and whole-blood storage conditions. However, as neutrophil elastase-specific degradation products did not increase and the complement-derived anaphylatoxin C3a was found in its inactivated form, C3a-desArg, these filtration-dependent changes apparently have little impact on the therapeutic quality of whole-blood-filtered fresh frozen plasma for transfusion.
Precautionary measures significantly reduced bacterial contamination rates of blood components. Long-term monitoring with standardized methods is appropriate to evaluate the cumulative effect of contamination-preventing measures.
Introduction
Standard treatment of congenital haemophilia A is based on replacement therapy with coagulation factor VIII (FVIII) products. A major complication of FVIII therapy is the occurrence of IgG alloantibodies (inhibitors) that neutralize FVIII activity.
Aim
The aim of the analysis was estimating the risk of high‐titre inhibitor associated with the second‐generation full‐length product compared to third‐generation full‐length product and other recombinant FVIII (rFVIII).
Methods
We conducted a combined analysis of individual patient data from three large studies in previously untreated patients (PUPs) with severe haemophilia A.
Results
A total of 1109 PUPs were treated from 1993 to 2013 including 787 PUPs treated from 2004 onwards (primary analysis cohort). A total of 322 patients (29.0%) developed an inhibitor, of which 192 (17.3%) a high‐titre inhibitor. In the primary analysis set, 29.9% of patients developed an inhibitor and 17.2% a high‐titre inhibitor. The combined analysis indicated a lower risk of high‐titre inhibitor development for the third‐generation rFVIII product compared to the second‐generation rFVIII product (primary analysis: adjusted hazard ratio (HR) = 0.72, 95% CI: 0.49 to 1.06). Adjusted HR for all inhibitor development was significantly lower for the third‐generation product compared to the second‐generation product.
Conclusion
The trend of an increased risk of inhibitor development in PUPs for one recombinant product illustrates that extrapolation from one recombinant factor VIII product to other products might not be justified.
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