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Giancarlo Castaman - One of the best experts on this subject based on the ideXlab platform.

  • clinicAl instrumentAl serologicAl And histologicAl findings suggest thAt HemophiliA b mAy be less severe thAn HemophiliA A
    Haematologica, 2016
    Co-Authors: D Melchiorre, Lidia Ibbamanneschi, Eloisa Romano, Mirko Manetti, Massimo Innocenti, Christian Carulli, Marco Matuccicerinic, Francesco Sofi, Silvia Linari, Giancarlo Castaman
    Abstract:

    Recent evidence suggests thAt pAtients with severe HemophiliA B mAy hAve A less severe diseAse compAred to severe HemophiliA A. To investigAte clinicAl, rAdiologicAl, lAborAtory And histologicAl differences in the ArthropAthy of severe HemophiliA A And HemophiliA B, 70 pAtients with HemophiliA A And 35 with HemophiliA B with At leAst one joint bleeding were consecutively enrolled. Joint bleedings ( 50), regimen of treAtment (prophylAxis/on demAnd), World FederAtion of HemophiliA, Pettersson And ultrAsound scores, serum soluble RANK ligAnd And osteoprotegerin were Assessed in All pAtients. RANK, RANK ligAnd And osteoprotegerin expression wAs evAluAted in synoviAl tissue from 18 HemophiliA A And 4 HemophiliA B pAtients. The percentAge of pAtients with either 10–50 or more thAn 50 hemArthrosis wAs greAter in HemophiliA A thAn in HemophiliA B ( P P =0.03, respectively), while thAt with less thAn 10 hemArthrosis wAs higher in HemophiliA B ( P vs. 20.2; P vs. 4.3; P versus HemophiliA B ( P P =0.006, respectively). Osteoprotegerin expression wAs mArkedly reduced in synoviAl tissue from HemophiliA A pAtients. In conclusion, the reduced number of hemArthrosis, the lower World FederAtion of HemophiliA And ultrAsound scores, And higher osteoprotegerin expression in serum And synoviAl tissue in HemophiliA B suggest thAt HemophiliA B is A less severe diseAse thAn HemophiliA A. Osteoprotegerin reduction seems to plAy A pivotAl role in the progression of ArthropAthy in HemophiliA A.

  • clinicAl instrumentAl serologicAl And histologicAl findings suggest thAt HemophiliA b mAy be less severe thAn HemophiliA A
    Haematologica, 2016
    Co-Authors: D Melchiorre, Lidia Ibbamanneschi, Eloisa Romano, Mirko Manetti, Massimo Innocenti, Christian Carulli, Marco Matuccicerinic, Francesco Sofi, Silvia Linari, Giancarlo Castaman
    Abstract:

    Recent evidence suggests thAt pAtients with severe HemophiliA B mAy hAve A less severe diseAse compAred to severe HemophiliA A. To investigAte clinicAl, rAdiologicAl, lAborAtory And histologicAl differences in the ArthropAthy of severe HemophiliA A And HemophiliA B, 70 pAtients with HemophiliA A And 35 with HemophiliA B with At leAst one joint bleeding were consecutively enrolled. Joint bleedings ( 50), regimen of treAtment (prophylAxis/on demAnd), World FederAtion of HemophiliA, Pettersson And ultrAsound scores, serum soluble RANK ligAnd And osteoprotegerin were Assessed in All pAtients. RANK, RANK ligAnd And osteoprotegerin expression wAs evAluAted in synoviAl tissue from 18 HemophiliA A And 4 HemophiliA B pAtients. The percentAge of pAtients with either 10-50 or more thAn 50 hemArthrosis wAs greAter in HemophiliA A thAn in HemophiliA B (P<0.001 And P=0.03, respectively), while thAt with less thAn 10 hemArthrosis wAs higher in HemophiliA B (P<0.0001). World FederAtion of HemophiliA (36.6 vs. 20.2; P<0.0001) And ultrAsound (10.9 vs. 4.3; P<0.0001) score meAn vAlues were significAntly higher in HemophiliA A pAtients. Serum osteoprotegerin And soluble RANK ligAnd were decreAsed in HemophiliA A versus HemophiliA B (P<0.0001 And P=0.006, respectively). Osteoprotegerin expression wAs mArkedly reduced in synoviAl tissue from HemophiliA A pAtients. In conclusion, the reduced number of hemArthrosis, the lower World FederAtion of HemophiliA And ultrAsound scores, And higher osteoprotegerin expression in serum And synoviAl tissue in HemophiliA B suggest thAt HemophiliA B is A less severe diseAse thAn HemophiliA A. Osteoprotegerin reduction seems to plAy A pivotAl role in the progression of ArthropAthy in HemophiliA A.

  • fActor viii gene f8 mutAtion And risk of inhibitor development in nonsevere HemophiliA A
    Blood, 2013
    Co-Authors: Corien L Eckhardt, Giancarlo Castaman, Alice S Van Velzen, Marjolein Peters, Jan Astermark, P P T Brons, Marjon H Cnossen, Natasja Dors, Carmen Escuriolaettingshausen, K Hamulyak
    Abstract:

    NeutrAlizing Antibodies (inhibitors) towArd fActor VIII form A severe complicAtion in nonsevere HemophiliA A, profoundly AggrAvAting the bleeding pAttern. IdentificAtion of high-risk pAtients is hAmpered by lAck of dAtA thAt tAke exposure dAys to therApeutic fActor VIII concentrAtes into Account. In the INSIGHT study, we AnAlyzed the AssociAtion between F8 mutAtion And inhibitor development in pAtients with nonsevere HemophiliA A (fActor VIII 2-40 IU/dL). This AnAlysis included 1112 nonsevere HemophiliA A pAtients from 14 centers in Europe And AustrAliA thAt hAd genotyped At leAst 70% of their pAtients. Inhibitor risk wAs cAlculAted As KAplAn-Meier incidence with cumulAtive number of exposure dAys As the time vAriAble. During 44 800 exposure dAys (mediAn, 24 exposure dAys per pAtient; interquArtile rAnge [IQR], 7-90), 59 of the 1112 pAtients developed An inhibitor; cumulAtive incidence of 5.3% (95% confidence intervAl [CI], 4.0-6.6) After A mediAn of 28 exposure dAys (IQR, 12-71). The inhibitor risk At 50 exposure dAys wAs 6.7% (95% CI, 4.5-8.9) And At 100 exposure dAys the risk further increAsed to 13.3% (95% CI, 9.6-17.0). Among A totAl of 214 different F8 missense mutAtions 19 were AssociAted with inhibitor development. These results emphAsize the importAnce of F8 genotyping in nonsevere HemophiliA A.

D Melchiorre - One of the best experts on this subject based on the ideXlab platform.

  • clinicAl instrumentAl serologicAl And histologicAl findings suggest thAt HemophiliA b mAy be less severe thAn HemophiliA A
    Haematologica, 2016
    Co-Authors: D Melchiorre, Lidia Ibbamanneschi, Eloisa Romano, Mirko Manetti, Massimo Innocenti, Christian Carulli, Marco Matuccicerinic, Francesco Sofi, Silvia Linari, Giancarlo Castaman
    Abstract:

    Recent evidence suggests thAt pAtients with severe HemophiliA B mAy hAve A less severe diseAse compAred to severe HemophiliA A. To investigAte clinicAl, rAdiologicAl, lAborAtory And histologicAl differences in the ArthropAthy of severe HemophiliA A And HemophiliA B, 70 pAtients with HemophiliA A And 35 with HemophiliA B with At leAst one joint bleeding were consecutively enrolled. Joint bleedings ( 50), regimen of treAtment (prophylAxis/on demAnd), World FederAtion of HemophiliA, Pettersson And ultrAsound scores, serum soluble RANK ligAnd And osteoprotegerin were Assessed in All pAtients. RANK, RANK ligAnd And osteoprotegerin expression wAs evAluAted in synoviAl tissue from 18 HemophiliA A And 4 HemophiliA B pAtients. The percentAge of pAtients with either 10–50 or more thAn 50 hemArthrosis wAs greAter in HemophiliA A thAn in HemophiliA B ( P P =0.03, respectively), while thAt with less thAn 10 hemArthrosis wAs higher in HemophiliA B ( P vs. 20.2; P vs. 4.3; P versus HemophiliA B ( P P =0.006, respectively). Osteoprotegerin expression wAs mArkedly reduced in synoviAl tissue from HemophiliA A pAtients. In conclusion, the reduced number of hemArthrosis, the lower World FederAtion of HemophiliA And ultrAsound scores, And higher osteoprotegerin expression in serum And synoviAl tissue in HemophiliA B suggest thAt HemophiliA B is A less severe diseAse thAn HemophiliA A. Osteoprotegerin reduction seems to plAy A pivotAl role in the progression of ArthropAthy in HemophiliA A.

  • clinicAl instrumentAl serologicAl And histologicAl findings suggest thAt HemophiliA b mAy be less severe thAn HemophiliA A
    Haematologica, 2016
    Co-Authors: D Melchiorre, Lidia Ibbamanneschi, Eloisa Romano, Mirko Manetti, Massimo Innocenti, Christian Carulli, Marco Matuccicerinic, Francesco Sofi, Silvia Linari, Giancarlo Castaman
    Abstract:

    Recent evidence suggests thAt pAtients with severe HemophiliA B mAy hAve A less severe diseAse compAred to severe HemophiliA A. To investigAte clinicAl, rAdiologicAl, lAborAtory And histologicAl differences in the ArthropAthy of severe HemophiliA A And HemophiliA B, 70 pAtients with HemophiliA A And 35 with HemophiliA B with At leAst one joint bleeding were consecutively enrolled. Joint bleedings ( 50), regimen of treAtment (prophylAxis/on demAnd), World FederAtion of HemophiliA, Pettersson And ultrAsound scores, serum soluble RANK ligAnd And osteoprotegerin were Assessed in All pAtients. RANK, RANK ligAnd And osteoprotegerin expression wAs evAluAted in synoviAl tissue from 18 HemophiliA A And 4 HemophiliA B pAtients. The percentAge of pAtients with either 10-50 or more thAn 50 hemArthrosis wAs greAter in HemophiliA A thAn in HemophiliA B (P<0.001 And P=0.03, respectively), while thAt with less thAn 10 hemArthrosis wAs higher in HemophiliA B (P<0.0001). World FederAtion of HemophiliA (36.6 vs. 20.2; P<0.0001) And ultrAsound (10.9 vs. 4.3; P<0.0001) score meAn vAlues were significAntly higher in HemophiliA A pAtients. Serum osteoprotegerin And soluble RANK ligAnd were decreAsed in HemophiliA A versus HemophiliA B (P<0.0001 And P=0.006, respectively). Osteoprotegerin expression wAs mArkedly reduced in synoviAl tissue from HemophiliA A pAtients. In conclusion, the reduced number of hemArthrosis, the lower World FederAtion of HemophiliA And ultrAsound scores, And higher osteoprotegerin expression in serum And synoviAl tissue in HemophiliA B suggest thAt HemophiliA B is A less severe diseAse thAn HemophiliA A. Osteoprotegerin reduction seems to plAy A pivotAl role in the progression of ArthropAthy in HemophiliA A.

Johnny Mahlangu - One of the best experts on this subject based on the ideXlab platform.

  • emicizumAb prophylAxis in HemophiliA A with inhibitors
    The New England Journal of Medicine, 2017
    Co-Authors: Johannes Oldenburg, Elena Santagostino, Johnny Mahlangu, Benjamin Kim, Christophe Schmitt, Michael U Callaghan, Guy Young, Rebecca Krusejarres, Claude Negrier
    Abstract:

    BAckgroundEmicizumAb (ACE910) bridges ActivAted fActor IX And fActor X to restore the function of ActivAted fActor VIII, which is deficient in persons with HemophiliA A. This phAse 3, multicenter triAl Assessed once-weekly subcutAneous emicizumAb prophylAxis in persons with HemophiliA A with fActor VIII inhibitors. MethodsWe enrolled pArticipAnts who were 12 yeArs of Age or older. Those who hAd previously received episodic treAtment with bypAssing Agents were rAndomly Assigned in A 2:1 rAtio to emicizumAb prophylAxis (group A) or no prophylAxis (group B). The primAry end point wAs the difference in bleeding rAtes between group A And group B. PArticipAnts who hAd previously received prophylActic treAtment with bypAssing Agents received emicizumAb prophylAxis in group C. ResultsA totAl of 109 mAle pArticipAnts with HemophiliA A with inhibitors were enrolled. The AnnuAlized bleeding rAte wAs 2.9 events (95% confidence intervAl [CI], 1.7 to 5.0) Among pArticipAnts who were rAndomly Assigned to emicizumAb prop...

  • phAse 3 study of recombinAnt fActor viii fc fusion protein in severe HemophiliA A
    Blood, 2014
    Co-Authors: Johnny Mahlangu, Hideji Hanabusa, Roshni Kulkarni, Jerry S Powell, Neil C Josephson, Margaret V Ragni, Pratima Chowdary, Ingrid Pabinger, Naresh Gupta, Patrick F Fogarty
    Abstract:

    This phAse 3 pivotAl study evAluAted the sAfety, efficAcy, And phArmAcokinetics of A recombinAnt FVIII Fc fusion protein (rFVIIIFc) for prophylAxis, treAtment of Acute bleeding, And perioperAtive hemostAtic control in 165 previously treAted mAles Aged ≥12 yeArs with severe HemophiliA A. The study

Moanaro Biswas - One of the best experts on this subject based on the ideXlab platform.

  • reprogrAmmed cd4 t cells thAt express foxp3 control inhibitory Antibody formAtion in HemophiliA A mice
    Frontiers in Immunology, 2019
    Co-Authors: Roland W. Herzog, Veronica Kuteyeva, Rania Saboungi, Cox Terhorst, Moanaro Biswas
    Abstract:

    CoAgulAtion FActor VIII (FVIII) replAcement therApy in HemophiliA A pAtients is complicAted by the development of inhibitory Antibodies, which often render the treAtment ineffective. Previous studies demonstrAted A strong correlAtion between induction of regulAtory T cells (Treg) And tolerAnce to the therApeutic protein. We, therefore, set out to evAluAte whether the Adoptive trAnsfer of FVIII-specific CD4+ Treg cells prevents inhibitor response to FVIII protein therApy. To this end, we first retrovirAlly trAnsduced FoxP3+ into FVIII-specific CD4+ cells, which resulted in cells thAt stAbly express FoxP3, Are phenotypicAlly similAr to peripherAlly induced Tregs And Are Antigen specific suppressors, As judged by in vitro AssAys. Upon trAnsfer of the FVIII-specific CD4+ FoxP3+ cells into HemophiliA A mice, development of inhibitory Antibodies in response to Administering FVIII protein wAs completely suppressed. Suppression wAs extended for 2 months, even After trAnsferred cells were no longer detectAble in the secondAry lymphoid orgAns of recipient AnimAls. Upon co-trAnsfer of FoxP3+-trAnsduced cells with the B cell depleting Anti-CD20 into mice with pre-existing inhibitory Antibodies to FVIII, the escAlAtion of inhibitory Antibody titers in response to subsequent FVIII protein therApy wAs drAmAticAlly reduced. We conclude thAt reprogrAmed FoxP3 expressing cells Are cApAble of inducing the in vivo conversion of endogenous FVIII peripherAl Tregs, which results in sustAined suppression of FVIII inhibitors cAused by replAcement therApy in recipient HemophiliA A AnimAls.

  • DAtA_Sheet_1_ReprogrAmmed CD4+ T Cells ThAt Express FoxP3+ Control Inhibitory Antibody FormAtion in HemophiliA A Mice.docx
    2019
    Co-Authors: Roland W. Herzog, Veronica Kuteyeva, Rania Saboungi, Cox Terhorst, Moanaro Biswas
    Abstract:

    CoAgulAtion FActor VIII (FVIII) replAcement therApy in HemophiliA A pAtients is complicAted by the development of inhibitory Antibodies, which often render the treAtment ineffective. Previous studies demonstrAted A strong correlAtion between induction of regulAtory T cells (Treg) And tolerAnce to the therApeutic protein. We, therefore, set out to evAluAte whether the Adoptive trAnsfer of FVIII-specific CD4+ Treg cells prevents inhibitor response to FVIII protein therApy. To this end, we first retrovirAlly trAnsduced FoxP3+ into FVIII-specific CD4+ cells, which resulted in cells thAt stAbly express FoxP3, Are phenotypicAlly similAr to peripherAlly induced Tregs And Are Antigen specific suppressors, As judged by in vitro AssAys. Upon trAnsfer of the FVIII-specific CD4+ FoxP3+ cells into HemophiliA A mice, development of inhibitory Antibodies in response to Administering FVIII protein wAs completely suppressed. Suppression wAs extended for 2 months, even After trAnsferred cells were no longer detectAble in the secondAry lymphoid orgAns of recipient AnimAls. Upon co-trAnsfer of FoxP3+-trAnsduced cells with the B cell depleting Anti-CD20 into mice with pre-existing inhibitory Antibodies to FVIII, the escAlAtion of inhibitory Antibody titers in response to subsequent FVIII protein therApy wAs drAmAticAlly reduced. We conclude thAt reprogrAmed FoxP3 expressing cells Are cApAble of inducing the in vivo conversion of endogenous FVIII peripherAl Tregs, which results in sustAined suppression of FVIII inhibitors cAused by replAcement therApy in recipient HemophiliA A AnimAls.

Hideji Hanabusa - One of the best experts on this subject based on the ideXlab platform.

  • fActor viii mimetic function of humAnized bispecific Antibody in HemophiliA A
    The New England Journal of Medicine, 2016
    Co-Authors: Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato, Katsuyuki Fukutake, Naoki Fukazawa, Koichiro Yoneyama, Hiroki Yoshida, Keiji Nogami
    Abstract:

    BAckgroundIn pAtients with severe HemophiliA A, stAndArd treAtment is regulAr prophylActic And episodic intrAvenous infusions of fActor VIII. However, these treAtments Are burdensome, especiAlly for children, And mAy leAd to the formAtion of Anti–fActor VIII AlloAntibodies (fActor VIII inhibitors). EmicizumAb (ACE910), A humAnized bispecific Antibody mimicking the cofActor function of fActor VIII, wAs developed to AbAte these problems. MethodsWe enrolled 18 JApAnese pAtients with severe HemophiliA A (with or without fActor VIII inhibitors) in An open-lAbel, nonrAndomized, interindividuAl dose-escAlAtion study of emicizumAb. The pAtients received subcutAneous emicizumAb weekly for 12 weeks At A dose of 0.3, 1.0, or 3.0 mg per kilogrAm of body weight (cohorts 1, 2, And 3, respectively). The end points were sAfety And phArmAcokinetic And phArmAcodynAmic profiles. An AdditionAl, explorAtory end point wAs the AnnuAlized bleeding rAte, cAlculAted As 365.25 times the number of bleeding episodes, divided by the n...

  • phAse 3 study of recombinAnt fActor viii fc fusion protein in severe HemophiliA A
    Blood, 2014
    Co-Authors: Johnny Mahlangu, Hideji Hanabusa, Roshni Kulkarni, Jerry S Powell, Neil C Josephson, Margaret V Ragni, Pratima Chowdary, Ingrid Pabinger, Naresh Gupta, Patrick F Fogarty
    Abstract:

    This phAse 3 pivotAl study evAluAted the sAfety, efficAcy, And phArmAcokinetics of A recombinAnt FVIII Fc fusion protein (rFVIIIFc) for prophylAxis, treAtment of Acute bleeding, And perioperAtive hemostAtic control in 165 previously treAted mAles Aged ≥12 yeArs with severe HemophiliA A. The study