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Biomedical subjects

C K Kasper

Publications and source records attributed to C K Kasper.

At least 37 records · Page 2Linked to original sources
PubMed1998

Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation.

Twenty six patients with mild or moderate haemophilia A and inhibitors are described. The inhibitor was detected at a median age of 33 years, after a median of 5.5 bleeding episodes. This usually following intensive replacement therapy. The median presenting inhibitor titre was antihuman 11.6 BU/ml, antiporcine 1.45 BU/ml. Plasma basal factor VIII level declined from a median of 0.08 IU/ml to 0.01 IU/ml following the inhibitor development. This caused spontaneous bleeding in 22 and a bleeding pattern similar to acquired haemophilia in 17. Bleeding was often severe and caused two deaths. The inhibitor disappeared spontaneously, or following immune tolerance induction, in 16 cases after a median of 9 months (range 0.5-46), with a return to the original baseline VIIIC level and bleeding pattern accompanied inhibitor loss. The inhibitor persisted in the remainder of the cases over a median period of 99 months (range 17-433 months) of follow-up. Inhibitors are an uncommon complication of mild haemophilia which frequently persist and may be associated with severe, life-threatening, haemorrhage. Forty-one percent of treated haemophilic family members had a history of factor VIII inhibitors, suggesting a familial predisposition to develop inhibitors in these kindreds. Sixteen patients from 11 families were genotyped. Seven different missense mutations affecting the light chain were detected and two in the A2 domain. Five patients from three families had a mutation causing a substitution of Trp2229 by Cys in the C2 domain which appears to predispose to inhibitor formation since 7 of the 18 affected individuals have a history of inhibitor development.

Adolescent↗
PubMed1996

Structural integrity of the gamma-carboxyglutamic acid domain of human blood coagulation factor IXa Is required for its binding to cofactor VIIIa.

This report describes the analysis of a novel mutant human factor IX protein from a patient with hemophilia B (factor IX activity <1%; factor IX antigen 45%). Enzymatic amplification of all eight exons of the factor IX gene followed by direct sequence analysis reveals a single nucleotide change (a guanine --> 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.

Adenine↗
PubMed1996

Safety profile of porcine factor VIII and its use as hospital and home-therapy for patients with haemophilia-A and inhibitors: the results of an international survey.

A multicentre retrospective survey was conducted to re-assess the use of porcine factor VIII (HYATE:C), its side effects and the selection of patients for regular or home-therapy. 15,152,000 units of HYATE:C were used by 154 patients. The median inhibitor cross-reactivity to porcine VIIIC of 137 patients was 15%, 27% of patients lacking cross-reactivity. An absent, intermediate or brisk specific antiporcine anamnestic response was observed in 29, 40 and 31% of patients respectively. Seven patients were treated on-demand as home-therapy for a median 6.2, range 1.5-13 years, 23 further patients were treated regularly in hospital for a median of 3, range 2-7 years. This group used 8,319,000 U of porcine VIIIC for 2,000 bleeding episodes. The incidence of transfusion reactions was 0.001%, 0.64% and 2.3%, for domiciliary infusions, infusions in multiply treated in-patients, and unselected in-patient infusions, respectively. The risk of reactions was dose-related. A post-infusion fall in platelet count was common, but usually transient and clinically insignificant. This was also dose-related (r = -0.64, p = 0.002). Marked reductions in platelet count were occasionally seen, usually with intensive replacement therapy. The relative lack of side effects observed amongst patients treated at home is attributable to the low, median 33 U/kg, dose used by this group. A subgroup of inhibitor patients, identifiable by their absent or modest anamnestic response to porcine factor VIII may be treated regularly and safely with this product in small doses, over a period of years.

Animals↗
PubMed1995

Safety of high doses of a monoclonal antibody-purified factor IX concentrate. The Mononine Study Group.

This report summarizes safety and efficacy information among patients treated with high doses (> 75 U/kg) of a monoclonal antibody-purified factor IX concentrate [coagulation factor IX (human) monoclonal antibody purified)] in two clinical trials. One hundred infusions of this factor IX concentrate at doses > 75 U/kg were administered to 35 patients, six of whom had experienced thrombotic complications during previous treatment with prothrombin complex concentrate. Hemostasis in all patients was rated as "excellent," and there were no thrombotic complications.

Adult↗
PubMed1995

Comparison of six commercial plasma references for factor VIII, factor IX and von Willebrand factor. On behalf of the Subcommittee for Factor VIII and IX of the Scientific and Standardization Committee of the ISTH.

Six brands of normal reference plasma produced in the United States, with assigned assay values for factor VII and IX and, in four instances, ristocetin cofactor and van Willebrand antigen, were assayed in nine coagulation laboratories in academic institutions in the same country. Differences in mean assays of reference plasmas, as a percent of labelled potency, were significant and were greater than differences among laboratories. Standard methods of assigning potency to commercial reference plasmas are recommended.

Antigens↗
PubMed1995

Molecular epidemiology of factor IX germline mutations in Mexican Hispanics: pattern of mutation and potential founder effects.

Germline mutations in patients with hemophilia B generally have arisen within the past 150 years. Evidence suggests that these germline mutations generally result from endogenous processes. However, a unique pattern would be expected if a population were exposed to a physiologically important germline mutagen since mutagens generally produce characteristic patterns, or "fingerprints", of mutation. To determine the pattern of mutation in Mexican Hispanics, the regions of likely functional significance in the factor IX gene were screened by dideoxy fingerprinting (ddF) in 31 families with hemophilia B. Mutations were found in 30 of these families. Haplotype analysis was performed on individuals with identical mutations to help distinguish independent, recurrent mutations from founder effects. Analysis of these 30 mutations, along with 7 mutations reported previously in Mexican Hispanic families, reveals a pattern of independent mutation that is similar to the pattern of mutation observed in 127 U.S. Caucasian families (p = 0.89). These results may reflect either an underlying pattern of germline mutation due to endogenous processes or the presence of an ubiquitous mutagen. Further analyses of the recurrent mutations revealed that two mutations, T296M and R248Q, accounted for 19% of the mutations found in the Mexicans. Haplotype data suggest that the multiple occurrences of T296M and R248Q are associated with founder effects and that screening for these mutations may allow rapid mutation detection and carrier diagnosis in a significant minority of Mexican families with hemophilia B, These two mutations also are associated with founder effects in the U.S, Caucasian population. However, the haplotypes are different in these two populations, indicating independent origins. The occurrence of identical founder mutations in distinct populations provides evidence for the previous hypothesis that the number of different mutations giving rise to mild or borderline mild/moderate hemophilia B is small compared to deleterious mutations causing more severe disease.

Factor IX↗
PubMed1994

Effect of low- and intermediate-purity clotting factor therapy on progression of human immunodeficiency virus infection in congenital clotting disorders. Transfusion Safety Study Group.

Low- and intermediate-purity clotting-factor therapies are believed to accelerate human immunodeficiency virus (HIV) progression in hemophiliacs through adverse immune effects of the other plasma proteins in the preparations. To investigate this postulate, we evaluated data from six clinical centers that observed persons with congenital factor deficiencies at 6-month intervals. The present analysis is based on HIV-infected subjects who received intermediate purity factor VIII or factor IX concentrates, or cryoprecipitate. For long-term outcome, we classified 374 subjects by the type and amount of treatment during our first year of observation, and determined the subsequent rate of progression to a CD4 count less than 200 cells/microL. A second analysis of this group used a repeated-measures, random-effect model that allowed for individual differences in CD4 decline. Finally, we compared short-term rates of change in CD4 count in each treatment interval of 525 subjects with the type and amount of factor therapy received in the same interval. There was no overall or dose-related deleterious effect of any form of treatment on CD4 trend. The CD4 decrease was less when cryoprecipitate was administered alone or combined with concentrate, but not significantly so. Our results counter the assertion that low- and intermediate-purity products accelerate the rate of CD4 decrease in HIV-1-infected hemophiliacs.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Hepatitis A virus transmission by blood products in the United States. Transfusion Safety Study Group.

To address the question of HAV prevalence and seroconversion in relation to clotting factor concentrates, we assayed an early serum for 339 hemophiliacs followed every 6 months by the Transfusion Safety Study in the period from mid-1985 until mid-1992. We found 58.4% positive around entry, with an age-specific prevalence that did not vary with age. In comparison to rates for anti-HIV-negative blood donors, they were significantly higher. Based on testing of subsequent sera, 11 hemophiliacs (7.8% of 141 susceptibles) changed their anti-HAV status from negative to positive. In 9 instances, positivity immediately followed the first dose of intravenous immune globulin. A possible seroconversion followed treatment with blood components, and a possible seroconversion followed intermediate-purity, solvent/detergent(SD)-treated factor VIII concentrate. Neither of these 2 patients was anti-HAV IgM positive, so that passively transferred antibody is possible. The high prevalence among hemophiliacs at entry must be further investigated by determining the expected background rate in a US population similar to the hemophilia patients, and by comparing anti-HAV prevalence associated with SD-treated and heat-inactivated concentrates.

Adolescent↗
PubMed1993

Comparison of the behavior of normal factor IX and the factor IX Bm variant Hilo in the prothrombin time test using tissue factors from bovine, human, and rabbit sources.

A subset of hemophilia B patients have a prolonged bovine-brain prothrombin time. These CRM+ patients are classified as having hemophilia Bm. The prolongation of the prothrombin time has been reported only with bovine brain (referred to as ox brain in some literature) as the source of thromboplastin; prothrombin times determined with thromboplastin from rabbit brain or human brain are not reported to be prolonged. Factor IX from a hemophilia Bm patient (factor IX Hilo) was isolated. The activity of factor IX Hilo was compared to that of normal factor IX in prothrombin time assays when the thromboplastin source was of bovine, rabbit, or human origin. Factor IX, either normal or Hilo, prolonged a prothrombin time regardless of the tissue factor source. However, unless thromboplastin was from a bovine source, this prolongation required high concentrations of factor IX. Further, factor IX normal was as effective as factor IX Hilo in prolonging the prothrombin time when rabbit or human thromboplastin was used. With bovine thromboplastin, factor IX Hilo was significantly better than factor IX normal at prolonging the prothrombin time. The amount of prolongation was dependent on the amount of factor IX Hilo added. In addition, the prolongation was dependent on the concentration of factor X present in the sample. The prothrombin time changed as much as 20 seconds when the factor X concentration was varied from 50% to 150% to normal (fixed concentration of factor IX Hilo). These results demonstrate the difficulty of classifying the severity of a hemophilia Bm patient based on the bovine brain prothrombin time unless both the factor IX and factor X concentrations are known.

Animals↗
PubMed1993

Germline mutations in the factor IX gene: a comparison of the pattern in Caucasians and non-Caucasians.

DNA samples of patients from around the world have been sequenced to precisely define the mutations in the factor IX gene resulting in hemophilia B. This study compares the patterns of independent mutation between 127 Caucasian and 44 non-Caucasian patients with hemophilia B. Caucasians and non-Caucasians are found to have similar patterns of transitions and transversions (both at CpG and at non-CpG sites) as well as insertions, deletions, microdeletions, and complex changes (chi 2 = 2.71, p = 0.922). An analysis of subgroups of transitions and transversions shows similar patterns among Caucasians and non-Caucasians (chi 2 = 2.98, p = 0.83). If the subset of non-Caucasian samples (24) in which the mutation is known to have occurred outside of the United States, Canada, and Europe (UCE) is compared to the Caucasian subset, the above conclusions are unchanged. The invariant nature of this pattern of mutation is most simply compatible with a predominance of endogenous processes or common mutagen exposure rather than mutagen exposure specifically associated with non-Caucasian status or non-Western lifestyle.

DNA Mutational Analysis↗
PubMed1993

Use of porcine factor VIII for surgical procedures in hemophilia A patients with inhibitors.

We have described the use of polyelectrolyte fractionated porcine factor VIII (HYATE:C, Porton Speywood Ltd, Wrexham, UK) to provide hemostasis in 45 patients with hemophilia A complicated by inhibitor antibodies. The cases were collected from hemophilia care providers in seven nations and represent some of the experience with porcine factor VIII generated over the past 12 years. A wide variety of procedures was performed with varying degrees of associated hemostatic challenge in a difficult treatment group. The patients were representative of the hemophilia population in general and ranged in age from 1 to 67 years. The results of our survey should encourage clinicians to consider use of porcine factor VIII to provide hemostatic coverage in hemophilia patients with inhibitors who require surgical procedures. Hemostatic coverage was satisfactory in the vast majority of episodes; there have been only a small number of easily controlled, well-tolerated adverse reactions, which were usually self-limited in nature. No life-threatening reactions to porcine factor VIII were seen during coverage for surgical procedures in our survey, although serious reactions can occur as noted above. This is remarkable, since surgical patients usually are treated with higher doses of porcine factor VIII for greater periods of time than most other hemophilic patients treated for hemarthroses or soft-tissue bleeding, for example. Thrombocytopenia in association with porcine factor VIII therapy has been a major concern since the first crude preparations were used in the 1950s. Modern series, however, note the incidence of thrombocytopenia in only a minority of patients treated with the current polyelectrolyte fractionated preparations of porcine factor VIII. In our series, thrombocytopenia with platelet counts of less than 150 x 10(9)/L occurred in 11 of 54 treatment episodes (20%). The mechanism for thrombocytopenia demonstrated in a previous study involves porcine von Willebrand factor, which may copurify with porcine factor VIII and cause platelet aggregation and/or clearance from the circulation. The phenomenon of thrombocytopenia appears to be related to the administration of high doses of porcine factor VIII in some cases; however, in other patients, it may develop inconsistently at modest doses. It may be that there are idiosyncratic differences between patients that determine the dose of porcine factor VIII likely to cause thrombocytopenia. As yet, there is no way to predict which patient will develop thrombocytopenia while being treated with porcine factor VIII.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Enzyme-linked immunoassays for CRM positive hemophilia A using monoclonal antibodies with defined epitopes.

Sensitive, monoclonal antibody-based, enzyme-linked immunosorbent assays (ELISAs) for plasma factor VIII (FVIII) antigen have been developed. The assays used five monoclonal anti-FVIII antibodies with known epitopes in four different pairwise combinations. The sensitivity of the assays was increased by use of the ELISA amplification method described by Bobrow et. al. (J. Immunol Methods 125:279, 1989). These assays can distinguish between CRM positive, CRM reduced and CRM negative hemophilia A. A total of 94 plasma samples from 78 different patients were screened and generally consistent results were obtained among the different assays. Such assays are potentially useful in the phenotypic and genotypic analysis of hemophilia A.

Antibodies, Monoclonal↗
PubMed1992

Hemophilia A due to mutations that create new N-glycosylation sites.

In studying the molecular defects responsible for cross-reacting material-positive hemophilia A, we have identified two patients in whom the nonfunctional factor VIII-like protein has abnormal, slower-moving heavy or light chains on SDS/PAGE. Both patients have severe hemophilia A (less than 1% of normal factor VIII activity) with a normal plasma level of factor VIII antigen. The molecular defects were identified by denaturing gradient gel electrophoresis screening of PCR-amplified products of the factor VIII-coding DNA sequence followed by nucleotide sequencing of the abnormal PCR products. In patient ARC-21, a methionine-to-threonine substitution at position 1772 in the factor VIII light chain creates a potential new N-glycosylation site at asparagine-1770. In patient ARC-22, an isoleucine-to-threonine substitution at position 566 creates a potential new N-glycosylation site at asparagine-564 in the A2 domain of the factor VIII heavy chain. The mobility of these chains on SDS/PAGE was normal after N-Glycanase digestion and procoagulant activity was generated--to a maximum of 23% and 45% of control normal plasma. Abnormal N-glycosylation, blocking factor VIII procoagulant activity, represents a newly recognized mechanism for the pathogenesis of severe hemophilia A.

Amidohydrolases↗
PubMed1992

Production and therapeutic use of a factor XI concentrate from plasma.

Factor XI deficiency is an uncommon bleeding disorder usually manifested by excessive bleeding after surgery or trauma. Until recently the only effective therapy has been fresh-frozen plasma (FFP) infusion. We describe the efficacy and safety of a new factor XI concentrate produced from human donor plasma by a modification of the method used for antithrombin III concentrate. The mean recovery of factor XI in the circulation measured on 62 occasions was approximately 91% of the injected dose, and the mean half-disappearance-time was 52 h. The concentrate was used for 31 invasive procedures in 30 patients, including 16 patients who had a definite bleeding tendency on previous occasions, with normal haemostasis being achieved in all but 1. Only 1 patient (previously experiencing allergy to FFP) experienced adverse effects during infusion. Monitoring of liver function tests and viral antibody status in suitable patients has shown no evidence of transmission of hepatitis viruses, HIV-1 or parvovirus B19. We conclude that this concentrate provides effective treatment for patients with factor XI deficiency. Preliminary results suggest safety from virus transmission, but this needs to be established in further studies of previously untreated patients.

Adolescent↗