thrombin generation assay (tga) as predictive test for haemostatic. effectiveness of fviii concentrates in haemophiliac a with inhibitors

Conditions: Severe Hemophilia A With Inhibitor

Summary: this is an observational, prospective, longitudinal, multicenter, cohort study designed with the scope to verify whether or not tga may predict effectiveness of different fviii concentrates class (devoid or rich of vwf) in patient affected by severe or moderately severe inherited haemophilia a and inhibitors.

rationale: hemophilia a is a serious and common hereditary bleeding disorder caused by deficiency of coagulation factor viii (fviii). patients with this disease are treated with recombinant factor viii or factor viii concentrates derived from plasma. administration of exogenous fviii in 15-35% of cases, cause the formation of antibodies to fviii (inhibitors) that neutralize the activity of factor viii, making the treatment ineffective.the development of inhibitors of factor viii (fviii) is the most serious and challenging complication of the treatment of hemophilia a and represents the highest economic burden for a chronic disease. therefore, research is making great efforts to optimize the best therapeutic approach for the disease. it has been observed that fviii inhibitors display a wide range of immunoreactivity when tested against different classes of fviii concentrates (with/without von willebrand factor -vwf). it has been demonstrated that the different inhibitors reactivity may correlate with different ability of inhibitors to impair thrombin generation, as tested by thrombin generation assay (tga). in these patients tga assay might be a tool to predict which fviii concentrate has the greater haemostatic effectiveness. it is also uncertain if the different classes of fviii used in iti protocols may have a different effectiveness in reducing the occurrence of bt bleedings and if this may correlate to lower reactivity, epitope specificity, vwf content and may be predicted by tga. it would be very helpful to be able to give an evidence based diagnostic and prognostic instrument, the tga, to aid physician to optimize the therapy for all inhibitors patients.

Eligibility criteria:
inclusion criteria: * diagnosis of inherited, severe (fviii:c \< 1%) or moderately severe haemophilia a (fviii ≤ 2%) * any age * ability to comply with study methods and willingness to participate to the study * written informed consent. for the low responders cohort - documented low anamnestic response after fviii exposure (fviii inhibitors titre \>0.6 and \ 0.6 and \ 5 bu over treatment with fviii) inclusion criteria for the high responders cohort * documented high response after fviii exposure (fviii inhibitors titre \> 5 bu/ml tested by bethesda assay, nijmegen modification). it will be included in this study those patients who are potential candidates to a first or rescue iti. * any historical peak ≥ 5 bu exclusion criteria: * diagnosis of acquired haemophilia * diagnosis of inherited mild haemophilia a (fviii \> 2%) * life expectancy lower than 1 year * psychiatric illness and any other conditions may impair ability to comply with study methods

Keywords: thrombin hemophilia inhibitors immunotolerance haemostatic fviii epitopes moderately severe hemophilia a with inhibitor