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F G Hill

Publications and source records attributed to F G Hill.

At least 37 records · Page 2Linked to original sources
PubMed1997

HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party.

The risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (> 10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion. HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies form 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA-DRB*1501, DQB1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7, 1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB1*01, DQB1*0501, DQA1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.

Chromosome Inversion↗
PubMed1997

Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product.

Use of high purity and recombinant factor VIII (FVIII) concentrates has been thought to be associated with an increased incidence of FVIII inhibitors in patients with severe haemophilia A. Comparison with comparable historical control groups has suggested that the true incidence of inhibitors in patients with severe haemophilia A was approximately 20-25%, similar to the incidence seen with new high purity and recombinant FVIII products. We have conducted a study of inhibitor development in a cohort of 37 boys with severe haemophilia A (VIII:C <2 u/dl) exposed only to a single FVIII concentrate (BPL 8Y) with no previous blood or blood product exposure. This factor VIII concentrate is an intermediate purity product with a specific activity of approximately 2 IU/mg protein and contains well preserved von Willebrand factor multimers. It is manufactured by conventional fractionation technologies and terminally dry heat treated at 80 degrees C for 72 h.

Antibodies↗
PubMed1996

Recommendations for the treatment of factor VIII inhibitors: from the UK Haemophilia Centre Directors' Organisation Inhibitor Working Party.

A strategy is described for the initial detection, management and elimination of factor VIII inhibitors arising in patients with congenital and acquired haemophilia A. It is suggested that children with severe haemophilia A should be screened every 3 months up to the age of 10 years for inhibitors using the Bethesda method. Factor VIII inhibitors arising in these patients should be abolished using immune-tolerance induction wherever possible. Such regimes should be started as early as possible, preferably when the inhibitor titre is < 10 Bethesda Units (BU)/ml, and should not be interrupted. High-intensity regimes are recommended for patients whose inhibitors exceed 10 BU. Autoantibodies to factor VIII giving rise to acquired haemophilia should be abolished using high-dose immunoglobulin or conventional immunosuppression. The choice of haemostatic agent for the treatment of severe bleeding should be based upon the clinical circumstances and the current inhibitor value, measured using both human and porcine factor VIII in the Bethesda assay. The past anamnestic response should also be considered when choosing treatment for minor bleeding episodes.

Blood Coagulation Factors↗
PubMed1995

The rarer inherited coagulation disorders: a review.

Of the inherited bleeding disorders, haemophilia A, haemophilia B and von Willebrand's disease make up together well over 80% of those registered with the UK Haemophilia Centre Directors. The common simple screening tests of coagulation may overlook some of the more rare disorders and it is clearly important that such uncommon bleeding disorders are excluded during the course of the investigation of children considered to be suffering from non-accidental injury. In this article, some of the rare inherited bleeding disorders are considered, including haemophilia B Leyden, deficiencies of factors VII, X, XI, and XII, as well as inherited defects of platelet number and function. Presenting features are described and recommendations regarding appropriate therapy given. In order to assist in advancing understanding of the biochemistry and molecular genetics of these disorders, clinicians are encouraged to share clinical information and, where appropriate, blood samples with interested research workers.

Blood Coagulation Disorders↗
PubMed1995

Association of changes in monocyte antigen presentation and cytokine production in haemophilic boys with treatment and blood-borne virus infection.

Aspects of monocyte function (antigen presentation and cytokine production (e.g. IL-1, IL-6) have been studied in a normal control population and three groups of haemophilic boys: group 1 HIV and HCV seronegative and treated only with a single heat-treated factor VIII (FVIII) concentrate; group 2 HIV seronegative but HCV seropositive; group 3 all HIV and HCV seropositive. Groups 2 and 3 have been previously treated with unheated and heated FVIII concentrate. Group 1 boys (HIV/HCV uninfected) showed no significant reduction in monocyte antigen presentation function nor IL-1 or IL-6 production when compared with a control population. Group 2 boys (HCV infected) showed a reduced monocyte antigen presentation activity (P < 0.05), but no significant reduction in IL-1 or IL-6 production. Group 3 boys (HIV and HCV infected) showed a significantly reduced monocyte antigen presentation activity (P < 0.001) and an impairment of IL-1 and IL-6 production (P < 0.05). A significant reduction of IL-1 and IL-6 production was only seen in the HIV and HCV infected haemophilic boys, implicating HIV as an aetiological agent. In contrast, reduced monocyte antigen presentation activity was seen in haemophilic boys with both HIV and HCV infection or HCV alone. The HIV and HCV seronegative boys had normal antigen presentation. The absence of immune modulation in haemophilic boys that have not acquired HIV and HCV infection suggests that chronic blood-borne virus infections as contributory to immune modulation seen in haemophiliacs with virus infections.

Adolescent↗
PubMed1995

Evidence for the aetiological role of blood-borne virus infections in causing reduced lectin-induced T-cell proliferation in haemophilic boys.

T-lymphocyte function, as expressed by polyclonal proliferation to lectin mitogens phytohaemagglutinin and concanavalin A, has been studied in a normal control population and three groups of haemophilic boys: group 1, HIV and HCV seronegative and treated only with a single heat-treated factor VIII (FVIII) concentrate; group 2, HIV seronegative but HCV seropositive; group 3, all HIV and HCV seropositive. Groups 2 and 3 have been previously treated with unheated and heated FVIII concentrate. Group 1 boys (HIV/HCV uninfected) showed no significant reduction in lymphocyte proliferation when compared with a control population. Group 2 and 3 boys showed an impaired response to these mitogens compared to group 1 boys and the control group. There was no relationship between FVIII concentrate received and proliferative response. The absence of immune modulation in haemophilic boys who have not acquired HIV and HCV infection implicates chronic blood-borne virus infections as the major contributory factors to impaired lymphocyte proliferative responses seen in haemophiliacs treated with large-pool concentrates. The presence of virus infections, such as HCV, may account for similar lymphocyte function abnormalities observed in previously described cohorts.

Adolescent↗
PubMed1995

The incidence of factor VIII inhibitors in the United Kingdom, 1990-93. Inhibitor Working Party. United Kingdom Haemophilia Centre Directors Organization.

Reports of all the factor VIII inhibitors arising in the United Kingdom in patients with haemophilia A during the years 1990-93 have been collated by the United Kingdom Haemophilia Centre Directors Organization. 32 new inhibitors were reported during this period, giving an average incidence of new inhibitors of 1.5 per 1000 patients registered per year. Although most occurred in patients with severe haemophilia under the age of 10, 29% occurred in patients whose VIIIC was > 3 iu/dl, and 38% in patients over the age of 10 years. The incidence of inhibitors rose during the study period, but this change was not statistically significant.

Adolescent↗
PubMed1993

HIV infection in haemophilia--a European cohort.

Ten haemophilia centres in northern Europe have pooled data on 202 haemophilic children who were infected with HIV between 1979 and 1986. All cases were under 16 years of age on 1 July 1985. The age at infection ranged from 1-15 years. Thirty seven cases (18%) had progressed to AIDS by 1 July 1991 and 15 of these have died. Persistent generalised lymphadenopathy has been noted in 102 patients of whom 18 (17%) have developed AIDS. Twenty three of the remaining patients (23%) have not. CD4+ T cell counts have fallen steadily. Of 36 patients who have had shingles since seroconversion, 19 (53%) had counts below 0.2 x 10(9)/l. Thirty five out of 145 patients without shingles (24%) had similar values. The mean IgA concentration in patients with CD4+ T cell counts above 0.5 x 10(9)/l was 2.38 g/l, between 0.2 and 0.5 was 3.07 g/l, and in those with CD4+ T cell counts below 0.2 x 10(9)/l the mean IgA concentration was 4.58 g/l. Treatment patterns have altered between 1989 and 1991, with increased use of zidovudine in patients without AIDS and a marked increase in primary prophylaxis against pneumocystis pneumonia. This has been associated with a decline in the incidence of pneumocystis as an indicator disease in new AIDS cases from 56% in 1989 to 20% in 1991. These observations indicate that persistent generalised lymphadenopathy does not worsen the outlook, but shingles does. Rising IgA concentrations are markers for disease progression. Modern prophylactic regimens are delaying the onset of indicator disease, but CD4 values continue to fall steadily.

AIDS-Related Complex↗
PubMed1991

Prognostic markers in diarrhoea-associated haemolytic-uraemic syndrome: initial neutrophil count, human neutrophil elastase and von Willebrand factor antigen.

The observed increase in plasma von Willebrand factor antigen (vWF:Ag) in patients with the haemolytic-uraemic syndrome is presumed to be secondary to endothelial damage, which is a central event in these diseases. As the prognostic value of such changes has not been previously evaluated, vWF:Ag has been measured in plasma from children reported to a national survey of haemolytic-uraemic syndrome. Human neutrophil elastase was also measured, as an initial neutrophilia has been shown to have prognostic value in diarrhoea-associated haemolytic-uraemic syndrome. Despite a significant elevation of plasma vWF:Ag concentration in these patients at presentation, the values did not correlate with the period of thrombocytopenia, the need for dialysis, or outcome. However, children with a poor outcome had significantly greater plasma elastase concentrations compared to those who had a good outcome.

Antigens↗
PubMed1991

Consistently normal CD4+, CD8+ levels in haemophilic boys only treated with a virally safe factor VIII concentrate (BPL 8Y)

Prospective biochemical, virological and selected immunological follow up has been done for up to 32 months on 15 previously untreated haemophilic boys following treatment with an intermediate purity dry heated factor VIII concentrate (BPL 8Y). Tests for liver function and antibodies to blood-borne viruses have been assessed monthly for the first year after starting treatment and thereafter every 2 months. All patients were immunized against hepatitis B and have not developed hepatitis B core antibodies and no boy has shown any rise in alanine transaminase level nor has anyone developed antibodies to hepatitis C (HCV). All patients have remained anti-HIV seronegative. T lymphocyte subsets have been measured approximately every 4 months and in no patient has there been a significant rise in CD8+ cells; one patient showed a significant decrease in CD4+ cells but these and all CD4+ values for the other boys remained within normal age related limits. Changes in CD4+ levels in this one boy were not related to the total amount of treatment received. This group of patients who appear not to have contracted HIV, hepatitis B or non A non B hepatitis following treatment with this intermediate purity factor VIII concentrate have also not shown any consistent changes in CD4+ or CD8+ cells, which have been recorded previously in frequently treated haemophiliacs.

Aging↗
PubMed1990

Qualitative and quantitative abnormalities of von Willebrand antigen in patients with diabetes mellitus.

Previous reported studies of vVWf antigen (vWf:Ag) in patients with diabetes mellitus have not shown qualitative abnormalities despite frequent documentation of raised vWf:Ag. Twenty two patients with established diabetes mellitus have been studied and qualitative abnormalities of vWf:Ag multimers were found in 10 patients who had poorer glycaemic control (as judged by plasma fructosamine) than the other 12 patients. Seven of the 22 patients were restudied after a 3 month period of improved glycaemic control and the vWf:Ag multimer abnormalities disappeared in 6 of these. Some of the structural abnormalities were accompanied by loss of vWf functional activity. As vWf:Ag is synthesised in the endothelial cell, vWf:Ag abnormalities during periods of poor glycaemic control may reflect endothelial cell damage with vWf:Ag release and possibly subsequent proteolysis.

Antigens↗
PubMed1990

Serological evidence that dry heating of clotting factor concentrates prevents transmission of non-A, non-B hepatitis.

A new test for antibodies specific for an agent causing non-A, non-B hepatitis (NANBH) was used to screen 45 children with coagulation disorders who received factor concentrates. It was found that the test results correlated with clinical evidence of NANBH and that heat treatment of concentrates (80 degrees C for 72 hours) appears to have prevented transmission of NANBH.

Child↗
PubMed1990

Clinical and laboratory evaluation of the treatment of von Willebrand's disease patients with heat-treated factor VIII concentrate (BPL 8Y).

Adequate rises of vWF:activity and satisfactory haemostasis have been obtained in six von Willebrand patients treated with heated 8Y factor VIII concentrate, despite multimeric analysis showing the concentrate to have an alteration in the proportions of the different vWF:Ag multimers including slight loss of the highest molecular weight multimers and an abnormal triplet. As heat-treated concentrates reduce the risk of transmitting blood borne viruses 8Y concentrate should be considered as a possible first line treatment of vWD patients in the U.K. if they do not have mild forms of type I von Willebrand's disease which can be treated with desmopressin (DDAVP) infusions.

Adolescent↗
PubMed1990

In vitro and in vivo inhibition of monocyte phagocytic function by factor VIII concentrates: correlation with concentrate purity.

Seven factor VIII concentrates of varying purity (specific activity 0.67-10 units factor VIII procoagulant activity (VIII: C)/mg protein) have been examined over a range of concentrations (0.5-0.005 u/ml factor VIII) to establish their effect on in vitro monocyte phagocytic function. All these products inhibited monocyte phagocytic function, but the monoclonally purified product tested was significantly less inhibitory than the others (P less than 0.05). The degree of inhibition observed was independent of the virus inactivation method used to increase product safety. However, comparison of these products of differing purity from the same manufacturer showed that the inhibitory effect decreased as product purity increased. In vivo studies of monocyte function following infusion of two of these factor VIII concentrates demonstrated inhibition of circulating monocytes. The possible role of product purity in modulating immune responses in haemophiliacs is discussed.

Cells, Cultured↗