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A L Bloom

Publications and source records attributed to A L Bloom.

At least 37 records · Page 2Linked to original sources
PubMed1989

Defective propeptide processing and abnormal activation underlie the molecular pathology of factor IX Troed-y-Rhiw.

Affected members of a South Wales haemophilia B family (from Troed-y-Rhiw) were shown by Western blotting and immunoperoxidase detection to have a factor IX molecule of higher than normal molecular weight which also shows impaired calcium binding. Gene cloning and DNA sequencing revealed the same arginine to glutamine mutation at position -4 of the propeptide that has been found in two previously described factor IX variants which circulate with the propeptide still attached. The mutation also abolishes a HaeIII restriction enzyme recognition site. A potential carrier was shown to be normal both by Western blotting and DNA studies. The way in which the attached propeptide interferes with normal factor IX function was investigated by activation studies with crude normal and patient factor IX Troed-y-Rhiw preparations using Western blotting and detection with iodinated immunopurified polyclonal antifactor IX serum. We demonstrate that the -4 mutation appears to block cleavage between the Arg145-Ala146 peptide bond in the activation peptide, thus preventing the normal activation of factor IX Troed-y-Rhiw. A small amount of normally processed factor IX is produced, implying that the -4 mutation does not completely prevent propeptide cleavage, thus accounting for the low levels of factor IX activity measured in the plasma of affected family members.

Base Sequence↗
PubMed1988

Carrier detection in 50 haemophilia A kindred by means of three intragenic and two extragenic restriction fragment length polymorphisms.

Carrier detection was attempted in 50 haemophilia A kindred by means of restriction fragment length polymorphism (RFLP) analysis using two linked and three intragenic probes. The sample comprised 330 individuals including 70 haemophiliacs, 45 obligate carriers and 100 possible carriers. Non-related haplotypes contained within the sample group were used to tabulate the intragenic RFLP allele frequencies. The linkage disequilibrium existing between the XbaI and Bc1I RFLP was shown to be less than previously reported, such that 69% of women are informative for at least one of these two polymorphisms. 36 women were subsequently diagnosed as carriers and 37 as being normal: in 52 of these, diagnosis was based either on intragenic RFLPs or linked RFLP plus strong phenotypic data, and was considered to be unequivocal; in the remaining 21, diagnosis was based on linked RFLPs alone and was considered to be probabilistic, with a 5-10% possible error rate. 27 of the possible carriers, either from families with sporadic haemophilia or from families where missing members precluded haplotype analysis, remained unassigned. 72% of the obligate carriers and firmly diagnosed carriers were heterozygous and phase known for at least one intragenic RFLP, whereas 6% were uninformative for the RFLPs for which they were examined. In 54 informative meioses, three recombinations between the factor VIII locus and the DX13 and/or ST14 loci were observed, giving a recombination rate of 5.5%. 15 prenatal diagnoses were carried out. Of the 11 male fetuses, six were shown to be affected and five to be normal. In three of four prenatal diagnoses where only a linked RFLP was informative, the result was confirmed by fetoscopy, fetal blood sampling, and factor VIII assay.

Alleles↗
PubMed1988

Studies on the stability of VIII:C during the manufacture of a factor VIII concentrate for clinical use.

The stability of VIII:C was investigated by monitoring samples taken at different points from a routine process for the manufacture of factor VIII concentrate and by examining the stabilising influence of a number of product formulations. Loss of VIII:C over process-finishing procedures (formulation, 0.22 micron filtration, dispensing) was associated with a citrate-induced inactivation which could be prevented by controlling the ionised calcium concentration of the solution. These results were obtained using a one-stage clotting assay but were not observed using a two-stage assay. No evidence for activation was found in vitro (e.g. by FPA generation and VIII:C stability) and the yield increase suggested by the one-stage assay was supported by results from a controlled clinical evaluation.

Antigens↗
PubMed1988

Inflammatory demyelinating polyneuropathy in a haemophiliac associated with human immunodeficiency virus infection, responding to high dose intravenous immunoglobulin.

We describe what we believe to be the first case of chronic inflammatory demyelinating polyneuropathy (CIDP) occurring in a haemophiliac infected with the human immunodeficiency virus (HIV), and the first patient to show a clinical response to treatment with high dose i.v. immunoglobulin. A 55 year old, severe haemophiliac, known to be positive for HIV antibody, presented with a short history of motor weakness and variable sensory loss in both lower limbs. Clinical examination, electrophysiology and sural nerve biopsy confirmed a diagnosis of CIDP. He was treated with a 4-day course of high dose i.v. immunoglobulin, given as a daily infusion. This resulted in dramatic improvement in his neurological status which was evident both clinically and functionally. We conclude that CIDP can occur in HIV-positive haemophiliacs as it does in homosexuals and drug abusers infected with the virus. We also suggest that high dose i.v. immunoglobulin may be effective in the treatment of this condition, especially when practical difficulties preclude the use of plasmapheresis and the use of immunosuppressive drugs is considered hazardous.

Demyelinating Diseases↗
PubMed1987

Epstein's syndrome: case report and survey of the literature.

A diagnosis of Epstein's syndrome was made in a young female with congenital macrothrombopathic thrombocytopenia, a nephropathy and mild sensorineural deafness. Previous case reports of this rare disorder are briefly reviewed and attention is drawn to the frequent association between inherited thrombocytopenia and renal disease.

Adult↗
PubMed1987

Heterogeneity of the factor IX locus in nine hemophilia B inhibitor patients.

DNA from nine hemophilia B patients who produce anti-factor IX inhibitors (antibodies), including two brothers, was analyzed by the Southern blotting method and hybridization with factor IX cDNA, intragenomic, and 3'-flanking probes. Two inhibitor patients were shown to have total deletions of the factor IX gene. Two other inhibitor patients, the brothers, were shown to have a presumably identical complex rearrangement of the factor IX gene involving two separate deletions. The first deletion is of approximately 5.0 kb and removes exon e. The second deletion is between 9 and 29 kb and removes exons g and h but leaves exon f intact. An abnormal Taq I fragment at one end of the deletion junctions acted as a marker for the inheritance of hemophilia B in the patients' family. Five other inhibitor patients have a structurally intact factor IX gene as detected by this method. Our studies indicate that whereas large structural factor IX gene defects predispose hemophilia B patients to developing an anti-factor IX inhibitor, the development of an inhibitor can be associated with other defects of the factor IX gene.

DNA↗
PubMed1986

Comparison of phenotypic assessment and the use of two restriction fragment length polymorphisms in the diagnosis of the carrier state in haemophilia B.

Carrier detection in haemophilia B has previously involved pedigree analysis and assessment of the coagulation phenotype. At best using these methods, carrier evaluation may be made with about 80% certainty (Orstavik et al, 1981). With isolation and cloning of the factor IX gene, DNA probes are now available to detect intragenic nucleotide changes. This study uses one such probe which detects restriction fragment length polymorphisms with the restriction endonucleases Taq 1 and Xmn 1. Seventy-eight individuals from eight haemophilia B kindred were initially evaluated for factor IXC and factor IXAg levels. DNA from these individuals was then digested with the two restriction enzymes and after Southern blotting, analysed for restriction fragment length polymorphisms (RFLPs) with the radiolabelled genomic probe. Four kindred proved informative with RFLP linkage assessment. In three families evaluation was possible with both Taq 1 and Xmn 1 polymorphic markers but in the fourth pedigree only Xmn 1 was informative. Using these techniques five potential carriers have been definitively assigned as either normal or carriers of the haemophilia B gene defect. Problems of phenotypic assessment are well illustrated in pedigree 4 where polymorphic linkage positively identified a carrier whose coagulation data were normal.

DNA Restriction Enzymes↗
PubMed1986

Inherited thrombocytopenia, elevated serum IgA and renal disease: identification as a variant of the Wiskott-Aldrich syndrome.

A kindred with X-linked hereditary thrombocytopenia in association with elevated serum IgA and a mild nephropathy is described. Thirteen males with thrombocytopenia were identified in three generations amongst 49 family members who were available for screening. Serious infective sequelae were absent but five patients had suffered from severe eczema since infancy. The platelet volume as measured by an automated counter and electron microscopy was reduced compared with normal and in vitro tests demonstrated minor abnormalities of immune function in three patients. The disorder is identified as a novel variant of the Wiskott-Aldrich syndrome and comparisons are made with previously described kindreds showing different patterns of expression.

Adult↗
PubMed1985

The application of a monoclonal antibody to factor VIII related antigen (VIIIRAg) in immunoradiometric assays for factor VIII.

A two site solid phase immunoradiometric assay (IRMA) for VIIIRAg has been developed using a monoclonal antibody as both the solid phase ligand and the radiolabelled antibody. A range of normal plasmas and von Willebrand's disease (vWd) plasmas has been assayed for VIIIRAg by this method and compared with VIIIRAg values measured by an IRMA using polyclonal antibodies and by immunoelectrophoresis and with ristocetin cofactor activity (VIIIRiCoF). It was found that the monoclonal IRMA correlated well with the polyclonal IRMA and the immunoelectrophoretic assay, but the correlation with the VIIIRiCoF assay was relatively poor, in spite of the strong inhibitory effect of the antibody on VIIIRiCoF activity.

Antibodies, Monoclonal↗
PubMed1985

Haemophilia and AIDS.

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Acquired Immunodeficiency Syndrome↗