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6. Gene-Centric Association Scans of Pleiotropic Immune-Mediated Disease Genes in the PATH Study Identify Novel Determinants of Factor VIII Inhibitor Risk in Hemophilia-A Patients and Confirm Race as an Independent Predictor

Author

Bouls, Ruayda, Almeida, Marcio A., Diego, Vincent P., Luu, Bernadette W., Rajalingam, Raja, Ameri, Afshin, Viel, Kevin R., Chitlur, Meera, Kim, Benjamin, Escobar, Miguel A., Williams-Blangero, Sarah, Kasper, Carol K., Almasy, Laura, Blangero, John, and Howard, Tom E.

Published
2023
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7. Inhibitors of factor VIII in black patients with hemophilia

Author

Vier, Kevin R., Ameri, Afshin, Abshire, Thomas C., Iyer, Rathi V., Watts, Raymond G., Lutcher, Charles, Channell, Cynthia, Cole, Shelley A., Fernstrom, Karl M., Nakaya, Shelley, Kasper, Carol K., Thompson, Arthur R., Almasy, Laura, and Howard, Tom E.

Subjects
African Americans -- Health aspects, African Americans -- Genetic aspects, Blood coagulation factor VIII -- Health aspects, Hemophilia -- Genetic aspects
Abstract

A study was conducted to determine the reasons that black patients with hemophilia A (factor VIII deficiency) develop inhibitors against factor VIII when administered as a replacement therapy. Results showed that mismatched factor VIII replacement therapy could be the reason for the development of anti-factor VIII alloantibodies.

Published
2009

12. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia

Author

Schwartz, Richard S., Abildgaard, Charles F., Aledort, Louis M., Arkin, Steven, Bloom, Arthur L., Brackmann, Hans H., Brettler, Doreen B., Fukui, Hiromu, Hilgartner, Margaret W., Inwood, Martin J., Kasper, Carol K., Kernoff, Peter B.A., Levine, Peter H., Lusher, Jeanne M., Mannucci, Pier M., Scharrer, Inge, MacKenzie, Mary A., Pancham, Nazreen, Kuo, Harng S., and Allred, Randy U.

Subjects
Blood coagulation factor VIII -- Health aspects, Hemophilia -- Drug therapy
Abstract

Hemophilia A is a relatively common genetic disorder that affects the blood clotting process, resulting in an tendency to hemorrhage. As an X-linked disorder, it occurs predominantly in men, affecting about 1 in 10,000 males. In its most severe form, it is a life-threatening illness. Patients with hemophilia A do not possess adequate activity of clotting factor VIII. The introduction of factor VIII treatment has resulted in a better quality of life and longer life expectancy for hemophilia patients. However, since the factor VIII has been obtained from blood, hemophilia patients have always been at higher risk for viral hepatitis and immunization against alloantigens. More recently, AIDS has been added as one of the diseases hemophiliacs may contract from contaminated factor VIII. This has provided an incentive to develop recombinant factor VIII, produced by bacteria using the human factor VIII gene. Since recombinant factor VIII does not come from human blood, the opportunity for the transmission of viral diseases is effectively eliminated. Two research groups have reported success with the cloning of factor VIII, one of the largest molecules cloned to date. Now, investigation of the effectiveness of recombinant factor VIII in treating 107 hemophiliacs has revealed that the new substance is safe and effective. The new recombinant factor VIII was no less effective or long-lasting in the blood than the traditional preparations. Furthermore, the new preparation proved to be no more antigenic than blood-derived factor VIII. As is the case with insulin and other protein factors, one of the major impediments to continued use of a factor VIII preparation is the development of antibodies. A small fraction of patients with hemophilia develop antibodies against factor VIII, which not only bind to the molecule, but inhibit its function. Such inhibitor antibodies developed in eight of the patients; the antibodies were strong in only one. This is comparable to the incidence of inhibitor antibodies seen using blood-derived factor VIII. (Consumer Summary produced by Reliance Medical Information, Inc.)

Published
1990

13. On the Role of F8 Sequence Mismatch and Class-II Human Leukocyte Antigen Binding in the Development of Neutralizing Antibodies ("Inhibitors") Directed Against Therapeutic Factor VIII Proteins (tFVIIIs): Evidence from the PATH Study

Author

Diego, Vincent P., primary, Luu, Bernadette W., additional, Ameri, Afshin, additional, Chitlur, Meera B., additional, Almeida, Marcio A., additional, Haack, Karin, additional, Kumar, Satish, additional, Dinh, Long V., additional, Mead, Henry, additional, Powell, Jerry S., additional, Escobar, Miguel A., additional, Rajalingam, Raja, additional, Williams-Blangero, Sarah, additional, Kasper, Carol K., additional, Almasy, Laura, additional, Cole, Shelley, additional, Blangero, John, additional, and Howard, Tom E., additional

Published
2019
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18. Results from an Association-Scan of the Extended MHC-Class-II Region Using Novel Association-Based Statistical Methods Establish That DQ Allotypes and Race Independently Influence the Risk of Factor VIII Inhibitor Development in Hemophilia-A Patients

Author

Ibarra, Paola, Almeida, Marcio A., Diego, Vincent P., Luu, Bernadette W., Viel, Kevin R., Rajalingam, Raja, Ameri, Afshin, Chitlur, Meera, Kim, Benjamin, Castillo, Grecia, Powell, Jerry S., Peralta, Juan M., Escobar, Miguel A., Williams-Blangero, Sarah, Blangero, John, Kasper, Carol K., Almasy, Laura, and Howard, Tom E.

Abstract

Hemophilia-A (HA) is caused by heterogeneous factor (F) VIII gene ( F8) mutations, variably deficient plasma FVIII activity and reduced to absent intrinsic-pathway amplification of coagulation. Infused therapeutic-FVIII-proteins (tFVIIIs) prevent bleeding in all HA patients but ~30% with severe HA and ~7.5% with non-severe HA become refractory with the development of neutralizing anti-tFVIII-antibodies called “FVIII inhibitors (FEIs)”. HLA-class-II (HLAII) molecules are critical for the development of FEIs and several association studies on different HA patient populations clearly implicate an important role for the highly polymorphic encoding HLA-D loci in the variable frequency of immunogenicity observed for tFVIIIs infused in different subjects with HA. However, the results from these studies were often conflicting, and none have undergone true independent confirmation. We use the ImmunoChip to genotype each subject in the PATH study simultaneously for the >900 single-nucleotide-variations (SNVs) distributed across the extended MHC-class-II (MHCII) region-which includes the classical- and non-classical-HLAII-genes and -pseudogenes-and then evaluated each independently for associations with FEI risk while accounting for the non-independence of data due to genetic relatedness and F8mutational heterogeneity using novel statistical methods. The “lifetime-FEI-status” of the 438 North American HA patients in PATH-whose racial-identity/ethnic-ancestry was self-reported as either black-African (n=200) or white-European (n=238)-was the dependent variable of interest. The F8-mutation data and a genetic-relatedness matrix were incorporated into a binary linear mixed model of genetic association with lifetime-FEI-status (Yes vs. No), with ‘Yes’ designating those patients having FEIs of either any titer (AT), i.e., >0.4 Bethesda Units (BUs) mL -1, or only high-titer (HT), i.e., ≥5.0 BUs mL -1. Following the analytical procedure used in prior studies designed to identify determinants of FEI risk, we conducted the extended-MHCII-region-wide association screen-against the 926 distinct SNVs with high-quality genotypes that passed QC-of lifetime-FEI-status on two groups of FEI-positive patients, i.e., those with AT-FEIs, or those with only HT-FEIs. HA patients in the HT-FEI group are suspected to be more homogeneous with respect to the underlying immunobiology as they appear clinically to have induced full adaptive immunity. In contrast, HA patients in the AT-FEI group are heterogenous as some will have transient FEIs, which spontaneously disappear, and others will have FEIs that may remain low-titer (LT) despite continued infusions of tFVIIIs. We found several SNPs that were not only significantly associated in both FEI groups-or significant and suggestive respectively in the HT- and AT-groups-but also increased in significance (i.e., their p-values decreased) under the HT analysis ( Figure 1). The latter observation indicates that these results correspond to true associations that became more apparent as sources of “noise” were removed upon going from the AT to HT analysis. These included a SNP in the 3'-UTR of DQB1(rs1049225, p-value=5.7E-7) and two intergenic HLAII region SNPs (rs2647012, p-value=1.1E-5; and rs2858324, p-value=1.1E-5). The DQB1 SNP reached an ImmunoChip-wide significance threshold in the HT analysis (i.e., a p-value <5.9E-7) and extended-MHCII-region-wide significance in the AT analysis (i.e., p-value <5.4E-5). Although the two HLAII-intergenic SNPs were not ImmunoChip-wide significant, they were significant across the MHCII region (i.e., p-value <5.4E-5). We found two SNPs that were significant and suggestive, respectively, in the HT- and AT-FEI analyses (rs9276189, p-value=1.3E-5; and rs2856717, p-value=3.3E-5), as well as one SNP that was significant in the HT-FEI analyses but not significant or suggestive in the AT analysis (rs9271366, p-value=1.9E-6). Our results establish that a novel DQB1 genetic variant is associated with FEI risk and confirm that HLA-DQ-allotypes and race independently influence the rate of FEI development in HA ( Figure 2).

Published
2023
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21. Structural Integrity of the -Carboxyglutamic Acid Domain of Human Blood Coagulation Factor IXa Is Required for Its Binding to Cofactor VIIIa

Author

Larson, Peter J., Stanfield-Oakley, Sherry A., VanDusen, William J., Smith, Kenneth J., Kasper, Carol K., High, Katherine A., and Monroe, Dougald M.

Abstract

This report describes the analysis of a novel mutant human factor IX protein from a patient with hemophilia B (factor IX activity adenine transition) in exon 2 at nucleotide 6409 which results in a glycine --> arginine substitution at amino acid 12 in the gamma-carboxyglutamic acid rich (Gla) domain of the mature protein. Factor IX was isolated by immunoaffinity chromatography from plasma obtained from the proband. The purified protein is indistinguishable from normal factor IX by polyacrylamide gel electrophoresis. Characterization of the variant in purified component assays reveals that it is activated normally by its physiologic activator factor XIa, but its phospholipid-dependent activation by the factor VIIa-tissue factor complex is diminished. In the presence of phospholipid and 5 mM Ca2+, the activities of variant and normal plasma-derived factor IX are similar; however, in the presence of activated factor VIIIa (intrinsic tenase complex), the normal augmentation of the cleavage of the specific substrate of factor IX, factor X, is not observed. The determination of the association constants for normal and variant factor IXa with factor VIIIa shows that the affinity of the activated variant factor IX for the cofactor factor VIIIa is 172-fold lower than normal. Competition studies using active site-inactivated factor IXas in the intrinsic tenase complex confirm that the defect in the variant protein is in its binding to factor VIIIa. We conclude that the structural integrity of the Gla domain of human factor IX is critical for the normal binding of factor IXa to factor VIIIa in the intrinsic tenase complex. In addition, a glycine at amino acid 12 is necessary for normal activation of factor IX by the factor VIIa-tissue factor complex.

Published
1996
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26. The Role of Immune-Response Gene Variants in Inhibitor Development in Black Patients with Hemophilia A.

Author

Howard, Tom E., primary, Cole, Shelley A., additional, Kasper, Carol K., additional, Ameri, Afshin, additional, Natarajan, Kavita, additional, Watts, Raymond G., additional, Manard, Valrie A., additional, Nakaya, Shelley M., additional, Kempton, Christine L, additional, Kennedy, Martina, additional, Kim, Benjamin, additional, Iyer, Rathi V., additional, and Almasy, Laura, additional

Published
2009
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29. Allelically Mismatched Replacement Therapy Due to Common African−Restricted Haplotypes of the Factor (F)VIII Protein May Underlie the Increased Incidence of FVIII Inhibitors Observed in Hemophilia−A Patients of African−Descent.

Author

Howard, Tom E., primary, Viel, Kevin R., primary, Fernstrom, Karl M., primary, Deshpande, Seema, primary, Ameri, Afshin, primary, Ali, M. Showkat, primary, Channell, Cynthia, primary, Iyer, Rathi V., primary, Watts, Raymond G., primary, Lutcher, Charles, primary, Nakaya, Shelley, primary, Kasper, Carol K., primary, Thompson, Arthur R., primary, Abshire, Thomas C., primary, and Almasy, Laura, primary

Published
2006
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41. Comparison of Six Commercial Plasma References for Factor VIII, Factor IX and von Willebrand Factor

Author

Kasper, Carol K, additional, Aronson, David L, additional, Davignon, George, additional, Foster, Paul, additional, Hillman-Wiseman, Carol, additional, Lusher, Jeanne M, additional, Manco-Johnson, Marilyn, additional, Meade, James B, additional, Montgomery, Robert R, additional, Rickies, Frederick R, additional, and White, Gilbert C, additional

Published
1995
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45. Authorship! Authorship!

Author

Green, Manfred S., Kasper, Carol K., Rennie, Drummond, and Flanagin, Annette

Subjects
Medical writing -- Authorship
Published
1994

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