FVIII/VWF complex displays a greater pro-hemostatic activity than FVIII preparations devoid of VWF. Study in plasma and cell-based models

Introduction. Plasma derived FVIII/VWF complex was reported to be less sensitive to inhibitors than FVIII preparations devoid of VWF. Aim. To compare the efficacy of FVIII/VWF complex (Fanhdi) and five different VWF-free FVIII preparations in restoring thrombin generation and activation of thrombin activatable fibrinolysis inhibitor (TAFI) in hemophilic plasma, with and without inhibitor, and in cell-based models. Methods. Experiments were performed in hemophilic plasma supplemented with inhibitory IgG or in plasma samples obtained from hemophilia A patients without (n=11) and with inhibitor (n=12). Thrombin generation was evaluated by calibrated automated thrombography (CAT) under standard conditions, in the presence of activated protein C (APC) or thrombomodulin (TM), and in cell based models including endothelial cells, either alone or in combination with platelets or tissue-factor-expressing blood mononuclear cells. The kinetics of TAFI activation was determined by a two stage functional assay in the absence and in the presence of APC. Results. In hemophilic plasma without inhibitor, Fanhdi enhanced thrombin generation and TAFI activation as well as recombinant (2nd-4th generation) and plasma derived FVIII preparations devoid of VWF. On the contrary, in plasma with inhibitor, Fanhdi displayed a greater ability to restore thrombin generation and TAFI activation under all tested conditions. Notably, in cell-based models including endothelial cells, Fanhdi proved more efficient than all other preparations in improving thrombin generation even in the absence of inhibitor. Conclusion. The greater pro-hemostatic activity of FVIII/VWF complex, either in hemophilic plasma with inhibitor or in the presence of endothelial cells, may offer therapeutic advantages.