TY - JOUR
T1 - Risk factors for inhibitor formation in haemophilia
T2 - A prevalent case-control study
AU - Ragni, M. V.
AU - Ojeifo, O.
AU - Feng, J.
AU - Yan, J.
AU - Hill, K. A.
AU - Sommer, S. S.
AU - Trucco, M. N.
AU - Brambilla, D. J.
AU - Brettler, Doreen
AU - Forand, Pat
AU - Geary, Peg
AU - Ewenstein, Bruce
AU - Sweeney, Carol
AU - Aledort, Louis
AU - Seremetis, Stephanie
AU - McCarthy, Joan
AU - DiMichelel, Donna
AU - Goldberg, Ilene
AU - Barron, Lloyd
AU - Hams, Arnette
AU - White, Gilbert
AU - Nielsen, Brenda
AU - Grimsley, Aime
AU - Cox-Gill, Joan
AU - Boyd, Andrea
AU - Green, David
AU - Boggio, Lisa
AU - Harris, Sandy
AU - Hoots, Keith
AU - Cantini, Madeline
AU - Buchanan, George
AU - Rutherford, Cynthia
AU - Dunnagan, Patricia
AU - Haire, William
AU - Hanlon, Elizabeth
AU - Kisler, Thomas
AU - Sally, Stabler
AU - Giambartolomei, Sheryl
AU - Arepally, Gowthami
AU - Shhwartz, Marsha
AU - Addiego, Joseph
AU - Matsunaga, Alison
AU - Chase, Beth
AU - Wolff, Laurence
AU - Thomas, Gregg
AU - Ingram, Robina
N1 - Funding Information:
F.S. and W.L. contributed equally to this paper. This work was supported as part of the Nanostructures for Electrical Energy Storage (NEES), an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Basic Energy Sciences under Award number DESC0001160. X.L. acknowledges the US Department of Energy's (DOE's) Office of Electricity Delivery & Energy Reliability (OE) (under Contract No. 57558) for the support of cathode development and full cell demonstration. F.S. was financially supported by China Scholarship Council (CSC).
PY - 2009
Y1 - 2009
N2 - Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case-control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200U per exposure, P <0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.O%) vs. zero of 57 (0%), P <0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P <0.001, and survival was shorter, 14 vs. 38yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P >0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. ≥120BU/mL, six vs. 16 months, P <0.01, but unaffected by tolerizing dose regimen, P >0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies.
AB - Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case-control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200U per exposure, P <0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.O%) vs. zero of 57 (0%), P <0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P <0.001, and survival was shorter, 14 vs. 38yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P >0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. ≥120BU/mL, six vs. 16 months, P <0.01, but unaffected by tolerizing dose regimen, P >0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies.
KW - Central nervous system bleeding
KW - Factor VIII
KW - Haemophilia
KW - Inhibitor
UR - http://www.scopus.com/inward/record.url?scp=69949099131&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69949099131&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2516.2009.02058.x
DO - 10.1111/j.1365-2516.2009.02058.x
M3 - Article
C2 - 19563499
AN - SCOPUS:69949099131
SN - 1351-8216
VL - 15
SP - 1074
EP - 1082
JO - Haemophilia
JF - Haemophilia
IS - 5
ER -