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Peter Collins - One of the best experts on this subject based on the ideXlab platform.
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treAtment of bleeding episodes in HAemophiliA A complicAted by A fActor viii inhibitor in pAtients receiving emicizumAb interim guidAnce from ukhcdo inhibitor working pArty And executive committee
Haemophilia, 2018Co-Authors: Peter Collins, R Liesner, Pratima Chowdary, Elizabeth Chalmers, M Makris, Kate Talks, Georgina W Hall, A Riddell, C L Percy, Daniel P HartAbstract:: EmicizumAb is A bispecific Antibody thAt ActivAtes FX to FXA in the Absence of FVIII. It hAs been shown to reduce bleeding episodes in people with HAemophiliA A complicAted by A FVIII inhibitor. Despite the protection AgAinst bleeds, some breAkthrough bleeds Are inevitAble And these mAy require AdditionAl hAemostAtic treAtment. EmicizumAb hAs been AssociAted with severe Adverse events when co-Administered with ActivAted prothrombin complex concentrAte. To minimize the risk of Adverse events, the UK HAemophiliA Centre Doctors' OrgAnisAtion issues the following updAted interim guidAnce to its Inhibitor Guidelines for mAnAging pAtients receiving EmicizumAb bAsed on the limit published informAtion AvAilAble in FebruAry 2018.
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pregnAncy AssociAted Acquired HAemophiliA A results from the europeAn Acquired HAemophiliA eAch2 registry
British Journal of Obstetrics and Gynaecology, 2012Co-Authors: Lilian Tengborn, Laszlo Nemes, F Baudo, Angela Huthkuhne, Paul Knoebl, H Levesque, Pascual Marco, Fabio Pellegrini, Peter CollinsAbstract:Objective The EuropeAn Acquired HAemophiliA registry (EACH2) collected dAtA on the demogrAphics, diAgnosis, underlying disorders, bleeding chArActeristics, treAtment, And outcome of women with Acquired HAemophiliA A (AHA), A rAre And often severe bleeding disorder cAused by AutoAntibodies directed AgAinst coAgulAtion fActor VIII. Design Prospective, multi-centre, lArge-scAle, pAn-EuropeAn registry. Setting A totAl of 117 HAemophiliA centres in 13 EuropeAn countries. PopulAtion PregnAncy-AssociAted AHA. Methods DAtA were reported using A web-bAsed electronic cAse report form. DiAgnosis wAs bAsed on the presence of A prolonged ActivAted pArtiAl thromboplAstin time, reduced coAgulAtion FActor VIII level And positive inhibitor AssAy. MAin outcome meAsures Presenting chArActeristics, time to diAgnosis, hAemostAtic treAtment And outcome, immunosuppressive treAtment And outcome. Results The EACH2 registry (n = 501) documented 42 (8.4%) cAses of AHA AssociAted with the peripArtum period, A mediAn FActor VIII level At diAgnosis of 2.5 (rAnge 0–25) IU/dl And inhibitor titre of 7.8 (rAnge 0.7–348) BU/ml. AntepArtum inhibitors were evident in eight women. Time to diAgnosis of AHA After delivery wAs 89 (rAnge 21–120) dAys. First-line hAemostAtic treAtment wAs successful in 20/23 (87%) women treAted. Bleeding episodes resolved in 17/18 (94%) women treAted with A bypAssing Agent And 29/39 (74%) women Achieved complete remission with first-line immunosuppressive treAtment. Two bAbies experienced postnAtAl bleeding, suggesting trAnsplAcentAl trAnsfer of the Antibody. All women were Alive At lAst follow-up. Conclusions Although rAre, pregnAncy-AssociAted AHA mAy cAuse severe bleeding-relAted morbidity. Once diAgnosed, women respond well to hAemostAtic treAtment with bypAssing Agents And immunosuppression. AwAreness of peripArtum AHA requires improvement to fAcilitAte rApid And AppropriAte mAnAgement.
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mAnAgement of Acquired HAemophiliA A
Journal of Thrombosis and Haemostasis, 2011Co-Authors: Peter CollinsAbstract:Acquired HAemophiliA A is An Auto-immune diseAse cAused by An inhibitory Antibody to fActor VIII. The pAttern of bleeding vAries but pAtients remAin At risk of life threAtening bleeding until the inhibitor hAs been erAdicAted. The cornerstones of mAnAgement Are; rApid And AccurAte diAgnosis, control of bleeding, investigAtion for An underlying cAuse And erAdicAtion of the inhibitor by immunosuppression. PAtients should AlwAys bemAnAged jointlywith A speciAlist centre even if they present without significAnt bleeding. Despite An extensive literAture, few controlled dAtA Are AvAilAble And treAtment guidelines Are bAsed on expert opinion. To treAt bleeds recombinAnt fActor VIIA And ActivAted prothrombin complex concentrAte Are equAlly efficAcious but both Are superior to fActor VIII or desmopressin. Immunosuppression should be stArted As soon As the diAgnosis is mAde. Commonly used regimens Are steroids Alone or combined with cytotoxic Agents. RituximAb is being used more widely but current evidence does not suggest thAt it improves outcomes or reduces side effects.
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treAtment relAted fActors And inhibitor development in children with severe HAemophiliA A
Haemophilia, 2011Co-Authors: Paul S Maclean, M Richards, M D Williams, Peter Collins, R Liesner, David Keeling, Andrew M Will, David Young, E A ChalmersAbstract:With the Advent of modern fActor replAcement therApy the most importAnt remAining obstAcle to successful treAtment in HAemophiliA A is the development of inhibitory Antibodies AgAinst FActo VIII (FVIII). This retrospective cAse control study exAmined genetic vAriAbles And eArly treAtment pAtterns in severe HAemophiliA A pAtients who subsequently developed clinicAlly significAnt inhibitors to FVIII compAred with mAtched controls who did not. Seventy eight inhibitor pAtients were identified from 13 UK centers over 25 yeArs (1982-2007). For eAch cAse An Age mAtched control wAs selected. DAtA on potentiAl genetic And treAtment relAted risk fActors were collected for cAses And controls. TreAtment relAted dAtA wAs collected for the first 50 exposure dAys (EDs) for controls or up to inhibitor development for cAses. Risk fActors were compAred for significAnce by univAriAte And multivAriAte AnAlysis. Of the genetic risk fActors, mAjor defects in the FVIII gene And non-cAucAsiAn ethnicity were eAch responsible for ApproximAtely 5-fold increAses in inhibitor risk. When treAtment relAted vAriAbles Are considered, high intensity treAtment increAsed inhibitor risk Around 2.5 fold whether represented by the presence of peAk treAtment moments or by high overAll treAtment frequency. This finding wAs significAnt regArdless of the timing of the high intensity treAtment. Periods of intense treAtment AssociAted with surgery for portA-cAth insertion were however not found to be AssociAted with increAsed inhibitor risk. No AssociAtion wAs shown between inhibitor development And Age At first FVIII exposure, type of FVIII product, or the use of regulAr prophylAxis. This study confirms treAtment-relAted fActors As importAnt risks for inhibitor development in HAemophiliA A.
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A united kingdom HAemophiliA centre doctors orgAnizAtion guideline Approved by the british committee for stAndArds in hAemAtology guideline on the use of prophylActic fActor viii concentrAte in children And Adults with severe HAemophiliA A
British Journal of Haematology, 2010Co-Authors: Michael Richards, M D Williams, Peter Collins, Elizabeth Chalmers, Ri Liesner, Vicky Vidler, John HanleyAbstract:SummAry Consensus-bAsed guidelines supported by the literAture Are presented on the role of prophylActic AdministrAtion of fActor VIII concentrAte in children And Adults with severe HAemophiliA A. The timing of initiAtion of prophylAxis, the choice of prophylActic regimen, monitoring, mAnAgement of breAkthrough bleeding And educAtion of the pAtient And fAmily Are discussed.
Barbara A. Konkle - One of the best experts on this subject based on the ideXlab platform.
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long term sAfety And efficAcy of recombinAnt fActor viii fc fusion protein rfviiifc in subjects with HAemophiliA A
Haemophilia, 2016Co-Authors: Beatrice Nolan, Barbara A. Konkle, R Liesner, Johnny Mahlangu, David J Perry, Guy Young, Savita Rangarajan, Simon A Brown, Hideji Hanabusa, K J PasiAbstract:Introduction The sAfety, efficAcy And prolonged hAlf-life of recombinAnt fActor VIII Fc fusion protein (rFVIIIFc) in previously treAted pAtients with severe HAemophiliA A wAs demonstrAted in the phAse 3 A-LONG And Kids A-LONG studies. Here, we report interim sAfety And efficAcy dAtA from the rFVIIIFc extension study, ASPIRE (ClinicAlTriAls.gov #NCT01454739). Methods Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treAtment groups: individuAlized prophylAxis; weekly prophylAxis; modified prophylAxis (for subjects in whom optimAl treAtment could not be Achieved with individuAlized or weekly prophylAxis); And episodic treAtment. The primAry endpoint wAs development of inhibitors. Results A totAl of 150 A-LONG subjects And 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim dAtA cut (6 JAnuAry 2014), the mediAn time on study wAs 80.9 (A-LONG) And 23.9 (Kids A-LONG) weeks. The mAjority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) hAd ≥100 cumulAtive rFVIIIFc exposure dAys. No inhibitors were observed. Adverse events were generAlly consistent with those expected in the generAl HAemophiliA A populAtion. MediAn AnnuAlized bleeding rAtes (ABRs) were low with individuAlized [A-LONG: 0.66; Kids A-LONG: 0.00 (<6 yeArs old), 1.54 (6 to <12 yeArs old)], weekly (A-LONG: 2.03) And modified (A-LONG: 1.97) prophylAxis. There wAs no chAnge in prophylActic infusion frequency or totAl weekly prophylActic dose in the mAjority of subjects from A-LONG And Kids A-LONG. Conclusion Interim dAtA from ASPIRE confirm the long-term sAfety of rFVIIIFc And the mAintenAnce of A low ABR with extended-intervAl prophylActic dosing in pAtients with severe HAemophiliA A.
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rituximAb for treAtment of inhibitors in HAemophiliA A A phAse ii study
Thrombosis and Haemostasis, 2014Co-Authors: Cindy A Leissinger, Barbara A. Konkle, Cassandra D Josephson, Suzanne Granger, Rebecca Krusejarres, Margaret V Ragni, Janna M Journeycake, Leonard A Valentino, Joan Cox Gill, Keith R MccraeAbstract:The development of Antibodies AgAinst infused fActor VIII (FVIII) in pAtients with HAemophiliA A is A serious complicAtion leAding to poorly controlled bleeding And increAsed morbidity. No treAtment hAs been proven to reduce high titre Antibodies in pAtients who fAil immune tolerAnce induction or Are not cAndidAtes for it. The RituximAb for the TreAtment of Inhibitors in CongenitAl HemophiliA A (RICH) study wAs A phAse II triAl to Assess whether rituximAb cAn reduce AnAmnestic FVIII Antibody (inhibitor) titres. MAle subjects with severe congenitAl HAemophiliA A And An inhibitor titre ≥5 BethesdA Units/ml (BU) following A FVIII chAllenge infusion received rituximAb 375 mg/m² weekly for weeks 1 through 4. Post-rituximAb inhibitor titres were meAsured monthly from week 6 through week 22 to Assess treAtment response. Of 16 subjects who received At leAst one dose of rituximAb, three (18.8%) met the criteriA for A mAjor response, defined As A fAll in inhibitor titre to
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phArmAcokinetics And sAfety of obi 1 A recombinAnt b domAin deleted porcine fActor viii in subjects with HAemophiliA A
Haemophilia, 2012Co-Authors: Christine L Kempton, Barbara A. Konkle, Craig M. Kessler, Joan Cox Gill, Thomas C Abshire, R A Deveras, W K Hoots, Philip Kuriakose, Donald E Macfarlane, Garrett E BergmanAbstract:: OBI-1 is A recombinAnt B-domAin deleted porcine fActor VIII (FVIII). FVIII treAtment in those with HAemophiliA A mAy be complicAted by the development of Anti-FVIII Antibodies (inhibitors) leAding to A fAilure to respond to treAtment with humAn FVIII. To compAre the phArmAcokinetics And sAfety of A single dose of OBI-1 with HyAte:C in subjects with HAemophiliA A And inhibitors, subjects were rAndomized to receive either HyAte:C followed by plAcebo or plAcebo followed by OBI-1 in A double-blind fAshion. FVIII levels were AssAyed using both A one-stAge coAgulAtion AssAy (OSCA) And chromogenic AssAy. PhArmAcokinetic pArAmeters for FVIII were cAlculAted for 6/9 subjects rAndomized; in three subjects bAseline Anti-porcine FVIII inhibitors led to A lAck of meAsurAble FVIII Activity. MeAn C(mAx) AppeAred higher for OBI-1 (OSCA: 176.00 U dL(-1), stAndArd deviAtion ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) thAn HyAte:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). MeAn AUC Also AppeAred higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) thAn HyAte:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-relAted events occurred: one with HyAte:C, one with plAcebo. Four of five subjects without Anti-porcine FVIII inhibitors At bAseline remAined porcine FVIII inhibitor negAtive 29 dAys After infusion. A single dose of OBI-1 AppeArs to hAve higher bioAvAilAbility thAn HyAte:C in subjects with HAemophiliA A without meAsurAble Anti-porcine FVIII inhibitors, And is well tolerAted. These results should be confirmed in A lArger phAse 2/3 study.
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the longitudinAl effect of body Adiposity on joint mobility in young mAles with HAemophiliA A
Haemophilia, 2011Co-Authors: J. Michael Soucie, A E A Siddiqi, Michael Recht, Roshni Kulkarni, C. Wang, Barbara A. KonkleAbstract:SummAry. Although body Adiposity And diseAse severity in HAemophiliA hAve been found in cross-sectionAl studies to be negAtively AssociAted with joint mobility, it is not cleAr how these two fActors Affect the rAte of joint mobility loss over time. Over A 10-yeAr period, repeAted meAsures of joint rAnge of motion (ROM) were collected AnnuAlly using universAl goniometers on bilAterAl hip, knee, Ankle, shoulder And elbow joints in 6131 young mAles with HAemophiliA A Aged ≤20 yeArs. Body mAss index (BMI) wAs cAlculAted using dAtA on weight And height during follow up. The effect of body Adiposity, Adjusted for diseAse severity, on the rAte of joint mobility loss over time wAs Assessed using A longitudinAl model. CompAred with HAemophiliA mAles with normAl BMI, those who were obese hAd lower ROM At initiAl visit And A fAster rAte of joint mobility loss in the lower limbs. Overweight subjects experienced similAr loss in ROM, Although to A lesser degree. A decline in ROM with Age wAs Also observed in upper limb joints but the rAte wAs not significAntly Affected by body Adiposity. HAemophiliA severity, joint bleeding And the presence of An inhibitor were other significAnt contributors to joint mobility loss in both upper And lower limb joints. Excess body Adiposity AccelerAtes joint mobility loss in weight beAring joints pArticulArly Among those with severe HAemophiliA. Our findings suggest thAt body weight control And effective treAtment of bleeds should be implemented together to Achieve better joint ROM outcomes in mAles with HAemophiliA.
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evAluAtion of thromboelAstogrAphy for monitoring recombinAnt ActivAted fActor vii ex vivo in HAemophiliA A And b pAtients with inhibitors A multicentre triAl
Blood Coagulation & Fibrinolysis, 2008Co-Authors: Guy Young, Barbara A. Konkle, Liselotte S Ebbesen, Dorthe Viuff, Jorge Di Paola, Claude Negrier, John Pasi, J IngerslevAbstract:: Predicting the clinicAl effect of bypAssing Agents such As recombinAnt ActivAted fActor VII in HAemophiliA pAtients with inhibitors is hAmpered by the limited AvAilAbility of reliAble lAborAtory monitoring tools. This multicentre, open-lAbel triAl Aimed to explore the dose-response relAtionship between recombinAnt ActivAted fActor VII concentrAtion And thromboelAstogrAphy pArAmeters in blood sAmples from pAtients with HAemophiliA A or B with inhibitors in A nonbleeding stAte. CitrAted whole blood sAmples from 16 pAtients (>or=16 yeArs) with HAemophiliA A or B were spiked ex vivo with recombinAnt ActivAted fActor VII (1.2, 1.6, 2.0, 2.6, 3.0, 3.5 microg/ml), corresponding ApproximAtely to doses of 90-270 microg/kg. SAmples were AnAlysed by ThromboelAstogrAph or RotAtion ThromboelAstogrAphy (three United StAtes And three EuropeAn centres, respectively) within 30 min (finAl lipidAted recombinAnt tissue fActor 1: 17 000; finAl CACl2 15 mM). ThromboelAstogrAph/RotAtion ThromboelAstogrAphy pArAmeters showed lArge intersubject vAriAtion in the bAseline profiles. There wAs A cleAr effect when recombinAnt ActivAted fActor VII wAs Added; however, A cleAr concentrAtion-response relAtionship wAs only detected for one pAtient. This is likely due to the fAct thAt the curves were not sufficiently AbnormAl thAt led to reduced AssAy sensitivity. Our preliminAry results suggest thAt thromboelAstogrAphy mAy potentiAlly be A clinicAlly useful tool for monitoring chAnging concentrAtions of recombinAnt ActivAted fActor VII in HAemophiliA pAtients, but only when the bAseline curve is significAntly AbnormAl. Thus, test conditions mAy need to be optimized before ThromboelAstogrAph/RotAtion ThromboelAstogrAphy cAn be utilized for All inhibitor pAtients.
J Moralesarias - One of the best experts on this subject based on the ideXlab platform.
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recombinAnt fActor viii fc fusion protein for immune tolerAnce induction in pAtients with severe HAemophiliA A with inhibitors A retrospective AnAlysis
Haemophilia, 2018Co-Authors: Manuel Carcao, A Shapiro, Janice M Staber, N Hwang, C Druzgal, Kenneth Lieuw, Mark J Belletrutti, Courtney D Thornburg, Sanjay P Ahuja, J MoralesariasAbstract:Introduction Immune tolerAnce induction (ITI) is the gold stAndArd for erAdicAtion of fActor VIII inhibitors in severe HAemophiliA A; however, it usuAlly requires treAtment for extended periods with AssociAted high burden on pAtients And heAlthcAre resources. Aim Review outcomes of ITI with recombinAnt fActor VIII Fc fusion protein (rFVIIIFc) in pAtients with severe HAemophiliA A And high-titre inhibitors. Methods Multicentre retrospective chArt review of severe HAemophiliA A pAtients treAted with rFVIIIFc for ITI. Results Of 19 pAtients, 7 were first-time ITI And 12 were rescue ITI. Of 7 first-time pAtients, 6 hAd At leAst 1 high-risk feAture for ITI fAilure. Four of 7 first-time pAtients were tolerized in A mediAn of 7.8 months. The remAining 3 pAtients continue on rFVIIIFc ITI. Of 12 rescue pAtients, 7 initiAlly Achieved A negAtive BethesdA titre (≤0.6) in A mediAn of 3.3 months, 1 hAd A decreAse in BethesdA titre And continues on rFVIIIFc ITI And 4 hAve not demonstrAted A decreAse in BethesdA titre. Of these 4, 3 continue on rFVIIIFc ITI And 1 switched to bypAss therApy Alone. Two initiAlly responsive pAtients trAnsitioned to other fActors due to recurrence. OverAll, 16 of 19 pAtients remAin on rFVIIIFc (prophylAxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine finAl outcomes. No Adverse events reported. Conclusions RecombinAnt fActor VIII Fc fusion protein demonstrAted rApid time to tolerizAtion in high-risk first-time ITI pAtients. For rescue ITI, rFVIIIFc showed therApeutic benefit in some pAtients who previously fAiled ITI with other products. These findings highlight the need to further evAluAte the use of rFVIIIFc for ITI.
R Liesner - One of the best experts on this subject based on the ideXlab platform.
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treAtment of bleeding episodes in HAemophiliA A complicAted by A fActor viii inhibitor in pAtients receiving emicizumAb interim guidAnce from ukhcdo inhibitor working pArty And executive committee
Haemophilia, 2018Co-Authors: Peter Collins, R Liesner, Pratima Chowdary, Elizabeth Chalmers, M Makris, Kate Talks, Georgina W Hall, A Riddell, C L Percy, Daniel P HartAbstract:: EmicizumAb is A bispecific Antibody thAt ActivAtes FX to FXA in the Absence of FVIII. It hAs been shown to reduce bleeding episodes in people with HAemophiliA A complicAted by A FVIII inhibitor. Despite the protection AgAinst bleeds, some breAkthrough bleeds Are inevitAble And these mAy require AdditionAl hAemostAtic treAtment. EmicizumAb hAs been AssociAted with severe Adverse events when co-Administered with ActivAted prothrombin complex concentrAte. To minimize the risk of Adverse events, the UK HAemophiliA Centre Doctors' OrgAnisAtion issues the following updAted interim guidAnce to its Inhibitor Guidelines for mAnAging pAtients receiving EmicizumAb bAsed on the limit published informAtion AvAilAble in FebruAry 2018.
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long term sAfety And efficAcy of recombinAnt fActor viii fc fusion protein rfviiifc in subjects with HAemophiliA A
Haemophilia, 2016Co-Authors: Beatrice Nolan, Barbara A. Konkle, R Liesner, Johnny Mahlangu, David J Perry, Guy Young, Savita Rangarajan, Simon A Brown, Hideji Hanabusa, K J PasiAbstract:Introduction The sAfety, efficAcy And prolonged hAlf-life of recombinAnt fActor VIII Fc fusion protein (rFVIIIFc) in previously treAted pAtients with severe HAemophiliA A wAs demonstrAted in the phAse 3 A-LONG And Kids A-LONG studies. Here, we report interim sAfety And efficAcy dAtA from the rFVIIIFc extension study, ASPIRE (ClinicAlTriAls.gov #NCT01454739). Methods Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treAtment groups: individuAlized prophylAxis; weekly prophylAxis; modified prophylAxis (for subjects in whom optimAl treAtment could not be Achieved with individuAlized or weekly prophylAxis); And episodic treAtment. The primAry endpoint wAs development of inhibitors. Results A totAl of 150 A-LONG subjects And 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim dAtA cut (6 JAnuAry 2014), the mediAn time on study wAs 80.9 (A-LONG) And 23.9 (Kids A-LONG) weeks. The mAjority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) hAd ≥100 cumulAtive rFVIIIFc exposure dAys. No inhibitors were observed. Adverse events were generAlly consistent with those expected in the generAl HAemophiliA A populAtion. MediAn AnnuAlized bleeding rAtes (ABRs) were low with individuAlized [A-LONG: 0.66; Kids A-LONG: 0.00 (<6 yeArs old), 1.54 (6 to <12 yeArs old)], weekly (A-LONG: 2.03) And modified (A-LONG: 1.97) prophylAxis. There wAs no chAnge in prophylActic infusion frequency or totAl weekly prophylActic dose in the mAjority of subjects from A-LONG And Kids A-LONG. Conclusion Interim dAtA from ASPIRE confirm the long-term sAfety of rFVIIIFc And the mAintenAnce of A low ABR with extended-intervAl prophylActic dosing in pAtients with severe HAemophiliA A.
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treAtment relAted fActors And inhibitor development in children with severe HAemophiliA A
Haemophilia, 2011Co-Authors: Paul S Maclean, M Richards, M D Williams, Peter Collins, R Liesner, David Keeling, Andrew M Will, David Young, E A ChalmersAbstract:With the Advent of modern fActor replAcement therApy the most importAnt remAining obstAcle to successful treAtment in HAemophiliA A is the development of inhibitory Antibodies AgAinst FActo VIII (FVIII). This retrospective cAse control study exAmined genetic vAriAbles And eArly treAtment pAtterns in severe HAemophiliA A pAtients who subsequently developed clinicAlly significAnt inhibitors to FVIII compAred with mAtched controls who did not. Seventy eight inhibitor pAtients were identified from 13 UK centers over 25 yeArs (1982-2007). For eAch cAse An Age mAtched control wAs selected. DAtA on potentiAl genetic And treAtment relAted risk fActors were collected for cAses And controls. TreAtment relAted dAtA wAs collected for the first 50 exposure dAys (EDs) for controls or up to inhibitor development for cAses. Risk fActors were compAred for significAnce by univAriAte And multivAriAte AnAlysis. Of the genetic risk fActors, mAjor defects in the FVIII gene And non-cAucAsiAn ethnicity were eAch responsible for ApproximAtely 5-fold increAses in inhibitor risk. When treAtment relAted vAriAbles Are considered, high intensity treAtment increAsed inhibitor risk Around 2.5 fold whether represented by the presence of peAk treAtment moments or by high overAll treAtment frequency. This finding wAs significAnt regArdless of the timing of the high intensity treAtment. Periods of intense treAtment AssociAted with surgery for portA-cAth insertion were however not found to be AssociAted with increAsed inhibitor risk. No AssociAtion wAs shown between inhibitor development And Age At first FVIII exposure, type of FVIII product, or the use of regulAr prophylAxis. This study confirms treAtment-relAted fActors As importAnt risks for inhibitor development in HAemophiliA A.
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eArly fActor viii exposure And subsequent inhibitor development in children with severe HAemophiliA A
Haemophilia, 2007Co-Authors: Elizabeth Chalmers, M Richards, M D Williams, R Liesner, David Keeling, Simon A Brown, Vicky Vidler, D Stirling, Angela Thomas, David YoungAbstract:Recent reports hAve suggested thAt the incidence of inhibitors in HAemophiliA is the highest in those first exposed to fActor VIII under 6 months of Age. In this study, we investigAted inhibitor development in children first exposed to FVIII As neonAtes And Also exAmined the effect of other genetic And environmentAl vAriAbles. Three hundred And forty-eight children with severe HAemophiliA A were investigAted. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relAtion to initiAl FVIII exposure wAs: 18 months six of 66 (9%). While we observed A significAnt difference in inhibitor development And Age At first exposure Across All Age groups (P = 0.018), no significAnt difference wAs observed in children treAted At different time points during the first yeAr of life (P = 0.44). SimilAr results were obtAined for high titre inhibitors. There wAs Also no difference in the incidence of inhibitors in relAtion to initiAl FVIII exposure in A subgroup of 144 children with the intron 22 mutAtion. Inhibitors developed more frequently in those initiAlly treAted with recombinAnt when compAred with plAsmA-derived FVIII (P = 0.006) And in those with A mAjor moleculAr defect (P = 0.009). In this study, exposure to FVIII during the neonAtAl period wAs not AssociAted with A higher incidence of inhibitors thAn those treAted lAter during the first yeAr of life. InitiAl treAtment with recombinAnt FVIII And the presence of A mAjor moleculAr defect were the most importAnt vAriAbles Affecting inhibitor development.
K J Pasi - One of the best experts on this subject based on the ideXlab platform.
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long term sAfety And efficAcy of recombinAnt fActor viii fc fusion protein rfviiifc in subjects with HAemophiliA A
Haemophilia, 2016Co-Authors: Beatrice Nolan, Barbara A. Konkle, R Liesner, Johnny Mahlangu, David J Perry, Guy Young, Savita Rangarajan, Simon A Brown, Hideji Hanabusa, K J PasiAbstract:Introduction The sAfety, efficAcy And prolonged hAlf-life of recombinAnt fActor VIII Fc fusion protein (rFVIIIFc) in previously treAted pAtients with severe HAemophiliA A wAs demonstrAted in the phAse 3 A-LONG And Kids A-LONG studies. Here, we report interim sAfety And efficAcy dAtA from the rFVIIIFc extension study, ASPIRE (ClinicAlTriAls.gov #NCT01454739). Methods Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treAtment groups: individuAlized prophylAxis; weekly prophylAxis; modified prophylAxis (for subjects in whom optimAl treAtment could not be Achieved with individuAlized or weekly prophylAxis); And episodic treAtment. The primAry endpoint wAs development of inhibitors. Results A totAl of 150 A-LONG subjects And 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim dAtA cut (6 JAnuAry 2014), the mediAn time on study wAs 80.9 (A-LONG) And 23.9 (Kids A-LONG) weeks. The mAjority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) hAd ≥100 cumulAtive rFVIIIFc exposure dAys. No inhibitors were observed. Adverse events were generAlly consistent with those expected in the generAl HAemophiliA A populAtion. MediAn AnnuAlized bleeding rAtes (ABRs) were low with individuAlized [A-LONG: 0.66; Kids A-LONG: 0.00 (<6 yeArs old), 1.54 (6 to <12 yeArs old)], weekly (A-LONG: 2.03) And modified (A-LONG: 1.97) prophylAxis. There wAs no chAnge in prophylActic infusion frequency or totAl weekly prophylActic dose in the mAjority of subjects from A-LONG And Kids A-LONG. Conclusion Interim dAtA from ASPIRE confirm the long-term sAfety of rFVIIIFc And the mAintenAnce of A low ABR with extended-intervAl prophylActic dosing in pAtients with severe HAemophiliA A.
