Evaluation Of The Efficacy Of Recombinant Activated Factorâ…¦ In Hemophilia Patients With Inhibitors

Background:Development of inhibitors to factor VIII/IX(FVIII/IX) is the most serious adverse event in replacement therapy of hemophilia patients. The introduction of bypassing agents such as recombinant activated factor VII(rFVIIa) has dramatically improved the management of bleeding episodes in such patients. Standard doses of90to120μg/kg given every2to3hours have provided hemostatic efficacy in many cases in the current literature. This approach in a prospective clinical investigation was effective in92%of treated bleeds after a mean of2.2injections. However, recent studies using a single dose of270μg/kg suggest that high-dose regimens are as effective and safe as standard-dose regimens. Pharmacologic doses of rFVIIa induce hemostasis not only in hemophilia patients, but also in patients with acquired hemophilia, congenital factor VII(FVII) deficiency, thrombocytopenia, Glanzmann thrombasthenia, et al. Recent years have witnessed treatment with rFVIIa can be monitored with global assays which assess overall clotting function. Both thrombelastography(TEG) and thrombin generation test(TGT) have been found to be particularly helpful for monitoring hemostatic therapy with rFVIIa in patients with inhibitors.Objective:1. To evaluate the efficacy and safety of rFVIIa used in different dose regimens in congenital/acquired hemophilia, congenital FVII deficiency patients.2. To evaluate the efficacy and safety of rFVIIa used in orthopaedic surgery in hemophilia patient with inhibitors.3. To assess the feasibility of TEG and TGT as tools in monitoring the response to rFVIIa in patients with inhibitors. To correlate the TEG parameters [time to clot(R), rate of clot formation(angel Alpha and K) and maximum amplitude of clot formation(MA)] and the TGT parameters [lag time, Peak, time to Peak and endogenous thrombin potential(ETP)] with the efficacy of rFVIIa and with the dose of rFVIIa used.Methods:1. rFVIIa were used in different dose regimens in acute bleeding episodes in congenital/acquired hemophilia patients with inhibitor and congenital FVII deficiency patients. 2. rFVIIa were used as the only hemostatic agent during an orthopaedic surgery in a hemophilia patient with inhibitors.3. PT、APTT、FVII:C、TEG and TGT were measured before and30minutes,2hours after the infusion of a therapeutic dose of rFVIIa.Results:1. Different doses of rFVIIa were given to treat9acute bleeding episodes in6congenital/acquired hemophilia patients with inhibitors. Seven bleeding episodes were treated with regular dose regimen(72.73-109.09μg/kg) while2bleedings were treated with a single high dose regimen(254.55-264.00μg/kg). The efficacy were85.7%(6/7) and50%(1/2) respectively. The total efficacy was77.8%(7/9).2. rFVIIa were successfully used to cover an orthopaedic surgery in a hemophilia patient with inhibitors.3. A single low dose(26μg/kg) of rFVIIa were used to successfully treat one acute bleeding episode in a congenital FVII deficiency patient.4. PT、APTT were shortened and FVII:C levels were elevated after infusion of rFVIIa. But there was no association between the results and clinical outcome.5. Whole blood clot-information recorded by TEG was improved in all patients following an infusion of rFVIIa. R and K were shortened while angle Alpha were increased. Most of the TEG profiles were not normalized. There was a dose dependent relationship between the changes of TEG parameters and rFVIIa. The association between the TEG profiles and clinical outcome were also observed.6. Thrombin generation(TG) curves showed an important increase in TG capacity following an injection of rFVIIa with a variable rate of correction in these patients. Lag time and time to Peak were shortened. ETP and Peak were increased. But these values were far below the reference range. The changes of TGT parameters appear to correlate with the clinical outcome.7. Great inter-individual variations of TEG and TGT parameters were observed.Conclusions:1. rFVIIa provided safe and effective hemostatic cover in acute bleeding episodes and during orthopaedic surgery in congenital/acquired hemophilia patients with inhibitors. Low dose regimen can achieve good hemostatic result in congenital FVII deficiency patients. 2. Inter-individual variation in the clinical efficacy of rFVIIa was observed. The reason is not clear yet.3. There was no association between PT/APTT/FVII:C results and clinical outcome of rFVIIa.4. The changes of TEG and TGT parameters appear to correlate with the clinical outcome. But due to the great inter-individual variations of TGT parameters, TEG might be a more reliable and appropriate method for monitoring treatment with rFVIIa.