Efficacy And Inhibitor Generation Of Recombinant Factor Ⅷ In Chinese Patients With Hemophilia A

Background and Objective:Hemophilia is an inherited bleeding disorder,which caused by the abnomalty of the amount of blood coagulation fator and the molecular structure.The patients have the tendency to bleed spontaneously or hurt lightly all over their life.Hemophilia A is an X-linked recessive inheritance hemorrhage disease caused by a deficiency of coagulation factorâ…§.Fâ…§locates in Xq28,is about 186kb, contains 26 exons and 25 introns.The 22 chromosome inversion can be seen in about 40-50%gravis type patients with hemophilia A.Fâ…§is one of the glycoproteins in plasma,in intrinsic coagulation system,with the help of Ca²⁺ and phospholipase,it works as a coenzyme to participate the Fâ…¨a's activation of Fâ…©.In plasma,the Fâ…§and Von Willebrand can form compound.The decrease or deficiency of Fâ…§:C is the reason why the Hemophilia A happened.Hemorrhage is the main syndrome of the disease.The patients have the tendency of hemorrhage spontaneously or when hurt lightly or after an operation.Replacement therapy is the most important method for Hemophilia A. Replacement therapy for haemophilia has evolved from the use of whole blood,fresh plasma and cryoprecipitate to the use of highly concentrated and purified plasma-derived and recombinant products.In the 1980s,the use of factorâ…§(Fâ…§) concentrates derived from plasma were associated with the transmission of blood-borne viruses,such as hepatitis A,B and C and human immunodeficiency virus(HIV) to the haemophilia population.This tragedy led,in part,to the development of recombinant Fâ…§(rFâ…§) products.Kogenate FS is a full-length rFâ…§product that is formulated with sucrose(rFâ…§-FS) as stabilizer,and produced without the addition of plasma-derived proteins during its purification and formulation,and treated with a solvent-detergent viral inactivation step.The generation of an inhibitor to Fâ…§(an antibody that neutralizes the coagulant activity of factor) following Fâ…§replacement therapy is the most serious treatment-related complication currently facing haemophilia patients;an inhibitor reduces the effectiveness of treatment,resulting in an increase in medical costs,and an increase in morbidity and mortality.Multiple clinical studies in North America and Europe have demonstrated the efficacy and safety of rFâ…§-FS in previously treated patients(PTPs) and previously untreated or minimally treated patients(PUPs or MTPs).In Japan and Canada,it is also reported that the Kogenate FS has better efficacy,safety and lower inhibitor development.In China,YangRenchi from the Tianjin Hemotology Centre had reported that the Kogenate FS has a better efficacy and safety.The inhibitor to Fâ…§contains two kinds,isoantibody and autoimmunity antibody.The majority of them are IgG antibody and the hypotype is IgG4,also we can see IgG1 hypotype.They haveκandλtwo kinds of light chain.IgM and IgA are less often to be seen.Known or suspected risk factors for the development of inhibitors to Fâ…§include:the severity of disease,the genetic mutation responsible for haemophilia, family history of inhibitors,ethnicity,age of first exposure to Fâ…§,molecular modi-fications of the Fâ…§molecule and the number of exposure days to Fâ…§. Early studies with plasma-derived Fâ…§indicated the prevalence of such inhibitors to be between 6 and 15%of all hemophilia A patients,or 21%for severe hemophilia patients.Initial results of studies of rFâ…§in previously untreated patients(PUPs) showed an incidence of 24-29%and caused speculation that the ultrapure recombinant produced in non-human mammalian cell culture resulted in an increased risk of inhibitor formation,and an earlier age of onset.Recent studies conducted in PUPs treated with both plasma- derived and recombinant Fâ…§products have generated data that now allow for meaningful comparisons of inhibitor risk with different products.In this study,we simply explore the efficacy,safety of Kogenate FS,and follow-up the inhibitor development in China.And we follow-up the change of inhibitor titre,the immunoglobulin class and concentration,and the change of genetype of the inhibitor positive patients.Data and Method:1.Case of patient Thirty Hemophilia A patients in our hospital,male, median age:23.5(age 1～44)..Of the 30 patients,8 are gravis type(＜1%),18 are middle type(1～5%),4 are light type(＞5%),the bleeding events are mainly happen in skin,muscle,articulus,upper gastrointestinal and hematuria;The exposure to Fâ…§: 3 are less than 20 days,6 are 20 to 100 days,21 are more than 100 days;all of the patients are antibody negative.We evaluate the efficacy and safety of eleven patients after the first infusion and observe the development of inhibitor in after 4 weeks,1 year and 2 years.The left 19 patients are only have a test for the antibody to Fâ…§. All of them are only use the Kogenate FS in the first four weeks,and the follow 2 years they can use what they like.2.Recombinant factorâ…§(Kogenate FS) Kogenate FS is a full-length rFâ…§product that is formulated with sucrose(rFâ…§-FS) as stabilizer,and produced without the addition of plasma-derived proteins during its purification and formulation,and treated with a solvent-detergent viral inactivation step,and its biological activity is similar to plasma-derived Fâ…§.Kogenate FS is ratified by our country's foods and drug surveillance administration(Batch No:27N19R1),donated by Bayer of the USA.The usage in our hospital is 13.6～42.5 IU/kg,slowly intravenous injection.3.Detection index:The blood routine,liver function and renal function, urine and stool routine,Fâ…§antibodies,Fâ…§activities,HBV,HCV and HIV were detected before and after the treatment in 11 of the 30 patients.The detection of Fâ…§activities were performed at 10 min and 60 min after the first dose.Then followed 2 years and detected the Fâ…§antibodies after 1 year,2 year and 4 weeks after the second medication.The other 19 patients only detected the Fâ…§antibodies before and 4 weeks after the medication.The detection of Fâ…§activity:By SYSMEX CA1500The detection of inhibitor:Bethesda Method,by SYSMEX CA1500The detection of IgG/IgA/IgM:Turbidimetry,by OLYMPUS AU5400The detection ofκ,λ:Nephelometry,by BN Prospec plasma analysator.The detection of IgG subtype:ELISA,by BIO-RAD4.Detection of therapeutic effect:Excellence:the hemorrhage is stopped, and the Fâ…§activity arises to the expected level after 10 and 60 minutes of the first infusion;Improve:the hemorrhage events are improved;Ineffective:the hemorrhage events are no better or more worse.Results:1.Validity:Of all the 30 patients,we used Kogenate FS 70 times,51294 IU.Although the median time of the first infusion of Kogenate.FS is 12h,much later than that of foreign countries,almost 86.7%patients used Kogenate FS less than 3 times to stop bleeding.So it is much more effective.It was observed that the Fâ…§activities at 10 min and 60 min after the first dose significantly increased,reached or near to the expected value and the hemorrhage was stopped.The effectiveness reached 100%.2.Safety:During the medication,there wre not any adverse effect.The blood routine, liver function and renal function,urine and stool routine,HBV,HCV and HIV are similar to those before medicatin.3.Inhibitor development:Before medication,all of the thirty patients are inhibitor negative.After the first infusion,only 1 patient produced Fâ…§inhibitor,the inhibitor titre is 256 BU.Two months later,the inhibitor titre goes down to 32 BU.So the incidence of inhibitor is 3.3%.11 patients are followed two years.Of the 2 years,they had also used other Fâ…§preparation.But at least 2 bleeding events were cured by Kogenate FS, 13.6-22.3 IU/Kg,one or two times.We find no inhibitor production.Our study indicates that the inhibitor production in our country is much lower than that of Europe,America and Japan.It is because in our country we used Kogenate.FS less frequent and lower dosage.4.The immunoglobulin class and subtype of inhibitorThe inhibitor positive patient is a boy,20 years old,without hemophilia family history.About 7 months old,he was diagnosed hemophilia A in the local hospital. After that,whenever the bleeding events happened,he was infused fresh plasma and cryoprecipitate.About 2 years ago,he began to use plasma-derived Fâ…§.After 4 weeks of the first infusion of Kogenate FS,he developed inhibitor,the titre is 256BU.Two months later,the inhibitor titre goes down to 32 BU.The blood routine, blood sedimentation rate BSR,liver function and renal function,autoantibody, anticardiolipin antibody,complement C3,C4,ASO,RF are normal.IgG 17.37g/L, The density of IgG is 17.37g/L,IgA 1.39g/L,IgM 1.64g/L;IgG1 7950mg/L,IgG2 5230mg/L,IgG3 580mg/L,IgG4 2583mg/L;κis 6.17g/L,λis 2.77g/L,lupus anticoagulant 38.7,APTT 116s.The patient has no other disease except hemophilia A.So the type of antibody is IgG.,and the subtype is IgG4,with bothκandλarised.Conclusion:1.Kogenate FS has better efficacy,safety and lower inhibitor production in the hemophilia A patients of China in this study(3.3%,1/30),and in the 2 years follow-up,we find no inhibitor increasing.2.In this study,we find only one inhibitor positive patient,the inhibitor titre is 256BU,which can go down quickly.The type of inhibitor is IgG.and IgG4 subtype, with bothκandλarised.