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B T Colvin

Publications and source records attributed to B T Colvin.

At least 19 recordsLinked to original sources
PubMed1998

Management of a premature infant with moderate haemophilia A using recombinant factor VIII.

The birth of a very premature infant with haemophilia A is a rare event. In this case report the problems posed in the management of a child with a factor VIII level of 0.03 IU mL-1 born at 28 weeks of gestation and weighing 1590 g are considered. The value of recombinant factor VIII, the pharmacokinetics of factor VIII in this situation and the importance of close cooperation between paediatricians and haematologists are discussed.

Factor VIII↗
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↗
PubMed1997

Haemophilia.

Although the nature of haemophilia has been understood for thousands of years, knowledge of its molecular genetics is recent. These X-linked bleeding disorders have diverse underlying DNA defects and, in 1992, DNA inversion within the X chromosome was found to explain half of the most serious cases of haemophilia A. The life-span and quality-of-life for patients with haemophilia had improved steadily throughout the early 1980s but the principal cause of death remained intracranial haemorrhage until the epidemic of HIV infection due to contaminated factor concentrates. Infection with hepatitis C virus is almost universal for patients treated with clotting factors before 1985. No curative treatment is available for hepatitis C at present. Knowledge of the transmission of viruses in concentrates has led to important developments in processing techniques to eliminate them. Recombinant technology has produced factor VIII and, more recently, factor IX concentrate which is likely to be very safe. Development of inhibitors to factor concentrates (especially factor VIII) remains one of the most serious complications of haemophilia. The variety of treatments available testifies to the lack of a single universally efficacious one. The use of prophylactic treatment has been conclusively demonstrated to result in a preservation of joint function in severely affected patients who might otherwise develop significant joint problems. The many facets of the care of patients with severe haemophilia, ranging from dental care to genetic counselling, can be advantageously co-ordinated in a haemophilia comprehensive care centre.

Acquired Immunodeficiency Syndrome↗
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↗
PubMed1996

Guidelines for the management of thrombophilia. Department of Haematology, The Royal London Hospital, Whitechapel, London, UK.

Although there are numerous risk factors for venous thromboembolic disease, the term 'thrombophilia' refers only to those familial or acquired disorders of the haemostatic system that result in an increased risk of thrombosis. The inherited thrombophilias include antithrombin III deficiency, resistance to activated protein C (factor V Leiden), protein C and protein S deficiencies as well as some rare forms of dysfibrinogenaemia. It is possible that other inherited conditions might also predispose to thrombosis. In contrast, when using the above definition, the antiphospholipid syndrome is the only genuine acquired thrombophilic state. Patients who have thromboembolic disease at a young age with no provoking event or who have a positive family history or whose thrombosis involves an unusual site should be investigated for thrombophilia. The management of a patient identified as having a laboratory abnormality associated with thrombophilia will depend on a variety of factors such as the patient's individual and family thrombotic history, the site of the thrombosis and the presence of other prothrombotic risk factors. The use of prophylactic anticoagulation during pregnancy and the puerperium requires particularly careful consideration in thrombophilic women. As more becomes known about the thrombophilias it will become possible to formulate more exact guidelines as to the management of these conditions.

Adult↗
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

Two antithrombin mutations in a compound heterozygote: Met20Thr and Tyr166Cys.

The molecular basis for a family with Type I antithrombin deficiency has been established. Amplification and sequencing of the antithrombin gene identified two mutations: Met20Thr (2523T-->C) within exon 2 and Tyr166Cys (5493A-->G) within exon 3a. Further analysis indicated that the propositus was a compound heterozygote but in addition provided evidence for phase disruption during the amplification and/or cloning procedure. The Met20Thr mutation appears to be a neutral mutation with no functional consequences. In contrast, the Tyr166Cys mutation is associated with a Type I phenotype.

Antithrombin III↗
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↗
PubMed1995

The affinity of IgG antibodies to gag p24 and p17 in HIV-1-infected patients correlates with disease progression.

The affinity of anti-gag antibody was studied for up to 9 years (1984-1993) in sera from 15 HIV-1+ patients with haemophilia. On the basis of their 1993 clinical status patients were divided into two groups: (i) patients who remained asymptomatic (n = 9); and (ii) those who progressed to AIDS between late 1987 and 1993. The affinity constants of antibody for p24 and p17 were determined by a double isotope fluid-phase radioimmunoassay; and the relationships between antibody affinity and titre, patient clinical course, CD4 cell counts and p24 antigenaemia were analysed. The affinity of p24- and p17-specific antibody was up to 100 times greater in asymptomatic patients than in patients who progressed to AIDS. Patients who developed AIDS either lost or failed to develop high-affinity antibodies early in the infection. Asymptomatic patients maintained high-affinity antibodies for several years; however, in some of these patients the affinity of anti-p24 and p17 antibodies subsequently fell later in the study period. The presence of low-affinity antibody and progressive reduction in the titre of specific antibody were earlier predictors of disease onset than CD4 cell counts. The failure to either develop or maintain high affinity gag-specific antibody suggests an early impairment of T helper function in individuals who progressed to AIDS. The presence of antibody of high affinity could be essential in controlling virus replication and the onset of AIDS.

Antibody Affinity↗
PubMed1994

A haemorrhagic platelet disorder associated with altered stimulus-response coupling and abnormal membrane phospholipid composition.

Haemorrhagic diatheses due to platelet function defects are a heterogenous and poorly understood group of conditions. We report the investigation of a female with a lifelong history of epistaxes, haemarthroses, menorrhagia and persistent iron-deficiency anaemia. Although platelet numbers and morphology were normal, platelet function was abnormal both in vivo and in vitro. Skin bleeding time was prolonged and aggregation thresholds in platelet-rich plasma to a variety of weak and strong agonists were increased. Platelet granule contents were normal and membrane glycoproteins GpIb and GpIIIa were present in normal amounts. Polyphosphoinositide metabolism and phosphatidic acid generation were diminished in thrombin-stimulated platelets, as was phosphorylation of the 47 kD substrate for protein kinase C and the 20 kD protein myosin light chain kinase, indicating impaired generation of the intracellular second messengers diacylglycerol and inositol trisphosphate due to diminished stimulated phospholipase C activity. Although intracellular free calcium, calmodulin activity and basal cAMP concentrations were normal, washed platelets showed increased cAMP accumulation following stimulation with prostaglandin E1 and forskolin. Platelet membrane lipid analysis revealed a reduction in plasmalogen phosphatidylethanolamine content. It is suggested that the membrane phospholipid abnormalities cause the abnormal platelet reactivity by interfering with signal transduction from platelet receptor, via intermediary G proteins, to phospholipase C and adenylate cylase. The bleeding tendency is likely to be a consequence of the altered stimulus-response coupling.

Blood Platelet Disorders↗