Abstract 41


Therapy with by-passing agents (BPA) in patients with hemophilia and inhibitors still lacks a laboratory test able to assess the hemostatic response, often unpredictable by clinical assessment. Thrombin generation assay (TGA) has been used in order to guide therapeutic choices in this setting by testing the response after spiking in vitro haemophilic plasma with BPA.


In this study, thrombin generation was assessed in vivo in platelet-rich (PRP) and platelet-poor (PPP) plasma with the addition of corn trypsin inhibitor in 15 patients with severe hemophilia A and high-responding inhibitors aged 5–73 years (median: 34). Four main parameters of the thrombin generation curve were evaluated: lagtime, endogenous thrombin potential (ETP), peak and time-to-peak. TGA was assessed in 11 patients prior, 30 minutes and 3 (rFVIIa 120 and/or 270 mcg/kg) or 6 (aPCC 80 IU/kg) hours after drug injection in a non-bleeding state and a minimum wash-out period of 48 hours from the last BPA injection. It was also assessed once daily prior and 30 minutes after BPA administration in 9 patients undergoing orthopaedic surgery (7 major and 2 minor procedures). Haemostatic treatment to cover surgical procedures and post-operative period was established irrespective of TGA measurements.


In the group of 11 patients who received BPA in a non-bleeding state, the values of the parameters of the TGA curve were highly variable between patients as well as in the same patient both in PRP and in PPP (ANOVA p<0.01). Overall, ETP increased after drug administration in all cases, with similar results obtained in PRP (median ETP increase: 585 nMxmin, IQR: 226–997) and PPP (median increase: 552 nMxmin, IQR: 415–1013) and no difference observed with respect to product type and/or doses used. In all patients who underwent surgery but one, no changes in the TGA curve were obtained after drug administration at least twice during a 7-days post-operative period. Moreover, no difference in TGA results were observed according to the type of BPA used, but few data referable to aPCC administration were available. Five post-operative bleeding complications were observed: 4 were major complications due to excessive bleeding for more than 5 days irrespective of treatment dosing intensification and 1 was a minor complication controlled by increasing BPA dosing; baseline ETP values as well as ETP increases after repeated BPA administrations in the presence of a bleeding complication were similar (in PRP and PPP) to those detected in the absence of bleeding complications. Moreover, for those patients who underwent TGA measurement both in a non-bleeding state and during surgery, there was no correlation between the values obtained in the two different settings.


Our data show that the high variability of TGA values observed between different subjects and in the same subject does not allow to use this test to predict and/or monitor the hemostatic efficacy of BPA in hemophilic patients with inhibitors.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.