Another unique variant pattern of intron 22 rearrangement in factor VIII gene seen in a hemophilia A family.
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Chromosome Inversion↗
Biomedical subjects
F G Hill
Publications and source records attributed to F G Hill.
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↗
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↗
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↗
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↗
Purpura fulminans due to protein S deficiency following chickenpox.
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Blood Proteins↗
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↗
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↗
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↗
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↗
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↗
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↗
HIV seroconversion in haemophilic boys receiving heat-treated factor VIII concentrate.
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Child↗
Transmission of human parvovirus B19 by coagulation factor concentrates.
The prevalence of antibody to human parvovirus B19 was determined in 86 children with congenital bleeding disorders. Forty-seven of 53 boys (89%) receiving non-heat-treated factor VIII or prothrombin complex concentrates were anti-B19 IgG positive compared with 38% of their age-matched controls and 48% of children treated with cryoprecipitate. Acute B19 virus infection occurred in 2 boys 3-4 weeks after they had received the same batch of commercial factor VIII concentrate. Of 11 susceptible children who had only received heat-treated National Health Service factor VIII concentrate (8Y), 1 acquired anti-B19 IgG. This suggests that 8Y heat-treated concentrate has a much reduced risk of transmitting B19 virus and, by implication, other less heat-stable viruses such as human immunodeficiency virus.
Adolescent↗
Growth in haemophilic boys after HIV infection.
Although failure to thrive has been documented as a major problem in babies with congenital HIV infection, there is little information on whether HIV affects growth in older children who become infected with HIV. The growth of 27 haemophilic boys, in whom HIV seroconversion was recorded between 1981 and 1986, has been assessed to see if the pattern changed after seroconversion. Height and weight recordings were analysed over a mean period of 9.2 years with a mean duration from HIV seroconversion of 4.5 years (range 2 to 6 years). Height standard deviation scores and ratio of weight to 50th centile for chronological age were calculated. No significant change in growth pattern as judged by height and weight has been observed within this group of boys after HIV seroconversion. Growth assessment continues to be evaluated to see if further progression of HIV disease changes growth pattern in these boys.
Adolescent↗
Premature chromosome condensation in childhood acute lymphoblastic leukaemia: correlation of proliferative potential index in blood and marrow.
The proliferative potential index (PPI), which is the proportion of all GI cells which are in late GI, has been shown to reflect disease state in patients with acute leukaemia. We have determined PPI in paired blood and marrow samples from children with acute lymphoblastic leukaemia (ALL) at different stages of the disease, and found a close correlation between blood and marrow PPI irrespective of disease stage. Therefore blood PPI can replace marrow PPI for monitoring disease control in ALL.
Adolescent↗
Vascular endothelial cell function and ultrastructure in thrombotic microangiopathy following allogeneic bone marrow transplantation.
We report studies on vascular endothelial function and ultrastructure in 2 cases of fatal cyclosporin (CS)-associated thrombotic microangiography following allogeneic bone marrow transplantation (BMT). Spontaneous vascular release of prostacyclin (PGI2) from a vein sample ex vivo was absent, and scanning electron microscopy (SEM) showed surface changes indicative of vascular endothelial damage (case 1). PGI2 release from cultured human umbilical vein endothelial cells incubated with patients' serum in vitro was normal in both cases. Plasma von Willebrand factor (vWF) antigen and ristocetin cofactor activity levels were raised in both patients, 5.06 and 7.02 (case 1) and 3.60 and 2.01 (case 2) (normal ranges 0.59-1.57 and 0.42-1.74 U/ml), respectively, but multimer patterns were normal. The SEM appearances coupled with the absent PGI2 release and raised vWF levels suggest that vascular endothelial damage is central to the pathogenic process in thrombotic microangiopathy following allogeneic BMT but the mechanisms appear to be distinct from those in the haemolytic uraemic syndrome and de novo thrombotic thrombocytopenic purpura. The precise role of CS in this process remains to be identified.
Adult↗
Safety trial of heated factor VIII concentrate (8Y).
Seventeen previously untreated boys with haemophilia A were treated with high purity heat treated factor VIII concentrate (8Y) for up to 36 months. Liver function tests were assessed monthly. No boy's serum has been shown to contain HIV antibodies and no increases in alanine transaminase activity have been detected. In only one patient was a single rise in aspartate transaminase activity noted, and this was without a corresponding rise in alanine transaminase. A second patient's serum contained hepatitis B core antibody transiently. It was thought likely in both cases that the abnormalities reflected intercurrent infections rather than disease associated with transfusion. The physical treatments used in the production of 8Y seem to inactivate the agent(s) responsible for non-A, non-B hepatitis and HIV transmission by transfusion of factor VIII has been abolished. There are, however, problems associated with conducting safety trials in young haemophiliac patients.
Acquired Immunodeficiency Syndrome↗