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Biomedical subjects

P H Bolton-Maggs

Publications and source records attributed to P H Bolton-Maggs.

At least 19 recordsLinked to original sources
PubMed2007

A cross-reactive material positive variant of coagulation factor XI (FXIP520L) with a catalytic defect.

Inherited deficiency of the trypsin-like protease factor (F) XI is associated with a mild to moderate bleeding diathesis. In most cases, FXI protein is reduced in plasma, and examples of dysfunctional circulating FXI variants are rare. We characterized the defect in one such variant with a proline to leucine substitution at residue 520. FXI Pro520 corresponds to chymotrypsin Pro161, and is conserved in most members of the chymotrypsin protease family. Recombinant FXI containing this substitution will be referred to as FXI(P161L). k(cat) for cleavage of chromogenic substrates and for activation of the natural FXIa substrate FIX is approximately 3-fold lower for activated FXI(P161L) (FXIa(P161L)) than for wild-type FXIa (FXIa(WT)), consistent with an abnormal protease active site. Inhibition of FXIa(P161L) by diisopropyl fluorophosphate is 2.4-fold slower than for FXIa(WT), suggesting distortion of the protease oxyanion hole. Binding to p-aminobenzamidine, a probe for the integrity of the S1 substrate-binding site, was similar for FXIa(WT) and FXIa(P161L). Rates of carbamylation of Ile16 were also similar for FXIa(WT) and FXIa(P161L), indicating that the critical salt bridge between Ile16 and Asp194 forms normally during protease activation. Cumulatively, the data demonstrate that Pro161 is required for normal active site oxyanion hole conformation in FXIa. Examination of the FXIa crystal structure and modeling studies indicate that Pro161 forms several hydrophobic contacts with adjacent amino acids that stabilize active site conformation. Leucine can be incorporated at position 161 in FXIa, but would not form the extensive stabilizing network of hydrophobic interactions formed by Pro161.

Aspartic Acid↗
PubMed2001

The nontreatment of childhood ITP (or "the art of medicine consists of amusing the patient until nature cures the disease").

The management of childhood acute idiopathic thrombocytopenic purpura is controversial, with recent guidelines highlighting the lack of suitable evidence upon which to base management decisions. Three European centers have used an expectant policy and results over the past decade demonstrate that this is safe and convenient for the majority of children. Adequate parental education about the condition from an experienced specialist is essential, together with open access for children should they develop any problems. A clinical stratification of such patients must be incorporated into any future trials, together with quality of life assessment to discover the impact of restrictions on lifestyle, particularly in adolescents with chronic ITP who may need a different approach.

Adolescent↗
PubMed2000

Factor XI deficiency and its management.

Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype. Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups. Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.

Blood Coagulation↗
PubMed2000

Pitfalls in the management of a child with mild haemophilia A and a traumatic hyphaema.

A 12-year-old boy presented with a traumatic hyphaema that failed to settle with the standard treatment. Subsequent investigation showed that despite a normal APTT, he had a low factor VIII:C. Treatment with DDAVP precipitated further bleeding despite correction of the fVIII:C to normal, possibly caused by the vasodilation induced by the therapy. Bleeding was effectively treated with recombinant fVIII concentrate. DDAVP may be contraindicated in mild Haemophilia and von Willebrand patients for treatment of traumatic hyphaema.

Child↗
PubMed2000

The diagnosis and management of hereditary spherocytosis.

Hereditary spherocytosis (HS) is relatively common in Caucasian populations; most individuals have mild or only moderate disease. There is commonly a family history and a typical clinical and laboratory picture so that the diagnosis is usually easily made without additional laboratory tests. Atypical cases may require measurement of membrane proteins and molecular genetics to clarify the nature of the membrane disorder. It is particularly important to rule out stomatocytosis because splenectomy is contraindicated because of the thrombotic risk. Mild HS can be managed without folate supplements and does not require splenectomy. Moderately and severely affected individuals are likely to benefit from splenectomy, which should be performed after the age of 6 and with appropriate counselling about the risk of infection. In all cases careful dialogue between physician, child and the family is essential. Laparoscopic surgery can result in shorter hospital stay and less pain.

Erythrocyte Membrane↗
PubMed2000

Idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura in children usually a self limiting disorder. It may follow a viral infection or immunisation and is caused by an inappropriate response of the immune system. About 20-30% of children will fail to remit over six months (chronic idiopathic thrombocytopenic purpura). This is more likely in older children, especially girls. The disease is reviewed with reference to diagnosis, investigation, and management options.

Bone Marrow Examination↗
PubMed1999

Bleeding problems in factor XI deficient women.

Factor XI deficiency affects both sexes. Some bleeding problems are specific to women, and have been overlooked in the past. Women with factor XI deficiency are prone to menorrhagia and to bleeding complications after childbirth. These may occur in women with partial deficiency, as well as in those with severe deficiency. Instrumental delivery and gynaecological surgery need careful planning in such women with close collaboration between the obstetrician and haematologist.

Adult↗
PubMed1998

Paroxysmal cold haemoglobinuria of childhood: a review of the management and unusual presenting features of six cases.

We report six cases of children presenting with paroxysmal cold haemoglobinuria occurring in a 3-year period in the north-west of England. In all six cases the onset of the illness was dramatic and its duration brief. We note the prominent red cell agglutination was evident in the blood film, the absence of a prompt reticulocyte response and a negative classical direct Donath Landsteiner test in each of these cases. The Direct Coombs Test (DCT) was positive when anticomplement reagents were used but high titres of free autoantibody were not demonstrated in the serum.

Child, Preschool↗
PubMed1998

The management of factor XI deficiency.

Factor XI deficiency leads to a more variable bleeding tendency than haemophilia A or B. Although severely deficient individuals are likely to bleed excessively especially after surgery in areas of the body with increased fibrinolysis, there is evidence that some partially deficient individuals are at risk of excessive bleeding. This will entail careful planning for surgery. Several therapeutic modalities are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs and desmopressin. The advantages and risks of these are considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used, it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.

Factor XI↗
PubMed1997

Assessment of UK practice for management of acute childhood idiopathic thrombocytopenic purpura against published guidelines.

BACKGROUND: Guidelines for management of acute immune thrombocytopenic purpura (ITP) in childhood were published in 1992. Regional audit in 1995 showed substantial variation in clinical practice not related to clinical differences in patient groups, which indicated a need for national audit. METHODS: Individuals aged from birth to their 16th birthday newly presenting with ITP were identified over 14 months by regular mailing of paediatricians and haematologists for case notification. Information was obtained from follow-up by a detailed questionnaire. FINDINGS: ITP was clinically mild and benign in 323 (76%) of 427 cases, including 181 (70%) of 260 cases with platelet counts below 10 x 10(9)/L. There were no deaths or intracranial haemorrhages. There was a substantial discrepancy between clinical practice and published guidelines: many children were admitted to hospital and received treatment unnecessarily; there was overuse of intravenous immunoglobulin (IVIg) as first-line therapy (94 children); children received steroids without marrow examination; and there was inappropriate use of platelet transfusions (41 with mild or moderate disease). INTERPRETATION: Our results indicate a need for change in practice.

Acute Disease↗
PubMed1997

Evaluation of two simplified methods for genotyping hepatitis C virus.

A number of different approaches have been used for genotyping hepatitis C virus (HCV). Two simplified methods were evaluated, both of which used polymerase chain reaction (PCR) to amplify products from the 5' non-coding region of HCV: non-isotopic restriction fragment length polymorphism (RFLP) analysis and type-specific PCR. Sixty-four viraemic patients suffering from chronic HCV infection were studied using these two techniques; 25/64 samples were further tested with a commercial serotyping ELISA based on synthetic NS4 antigen (Murex, U.K.). The results of the three typing methods were generally in agreement with each other. When only the predominant genotype identified by each method was analysed, the 3 methods had 100% agreement. RFLP did not detect any mixed infections and it was unsuccessful in 16/64 (25%) samples. Both type-specific PCR and serotyping ELISA detected mixed infections. However, serotyping ELISA did not give typeable results in 7/25 (28%) samples, whereas type-specific PCR gave typeable results in all 64 samples. Type-specific PCR detected more mixed infections than serotyping ELISA. Direct sequencing of four PCR products with indeterminate RFLP confirmed changes in restriction enzyme recognition sites. The sequences also confirmed the validity of the predominant genotype in cases of apparent mixed infections. It is possible that some of these cases were artefacts as a result of quasispecies.

Base Sequence↗
PubMed1996

Factor XI deficiency.

That factor XI has a role in normal blood coagulation is evidenced by the fact that patients with deficiency are prone to excessive bleeding after haemostatic challenge. The role of factor XI in physiological processes has become clearer since the discovery that it is activated by thrombin; this fact has contributed to a revised model of blood coagulation. Factor XI deficiency is particularly common in Ashkenazi Jews. Bleeding is typically provoked by surgery in areas of increased fibrinolysis, and is not restricted to individuals with severe deficiency. The bleeding tendency is variable and the reasons for this are not fully understood, although in severe deficiency there is some correlation between phenotype and genotype. The factor XI gene is 23 kb long, and two mutations are responsible for most factor XI deficiency in the Ashkenazi population. A total of 13 mutations have thus far been published. Factor XI deficient patients may need specific therapy to cover surgery and dental extractions. Although a factor XI concentrate is available there have been recent reports of coagulation activation and thrombosis indicating that it should be used cautiously. Fresh frozen plasma may be an acceptable alternative in some situations.

Amino Acid Sequence↗
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

Identification of two novel mutations in non-Jewish factor XI deficiency.

We have studied two heterozygous unrelated CRM- non-Jewish FXI-deficient patients. Neither of the patients carries a previously described mutation. Their FXI genes were screened by SSCP analysis following PCR amplification of each exon and the flanking intronic sequences. DNA fragments showing aberrant mobility were cloned and sequenced. The following mutations were identified: in case 1, a T to G transition in exon 12 results in the substitution of Phe-442 by Val (FXI-F442V); in case 2 a C to A transition in exon 5 results in the substitution of Cys-128 by a nonsense codon (FXI-C128X). The missense mutation results in a substitution within the protease domain of FXI. Molecular modelling locates this residue in a structurally conserved region of the protease domain and the amino acid substitution may therefore interfere with either chain folding and subsequent secretion or the stability of the protein in plasma. We conclude that the mutations which we have identified are responsible for the inherited abnormality in these patients.

Adult↗
PubMed1995

The high frequency of the -6G-->A factor IX promoter mutation is the result both of a founder effect and recurrent mutation at a CpG dinucleotide.

We report a new Liverpool family with a mild haemophilia B Leyden phenotype caused by a -6G-->A mutation in a CpG dinucleotide in the promoter of the clotting factor IX gene. This mutation had previously been identified in three other U.K. pedigrees and six others worldwide. To investigate whether these mutations were of independent origin, the haplotype was determined for eight polymorphic loci, within or immediately adjacent to the factor IX gene, for nine of the 10 existing patients. Six probands had identical haplotypes, including all four U.K. probands, suggesting that they arose from a common founder. The other three probands differed in haplotype from the common haplotype, and from each other, suggesting that they were independent mutations at this CpG dinucleotide.

Child↗
PubMed1995

Definition of the bleeding tendency in factor XI-deficient kindreds--a clinical and laboratory study.

Individuals with severe factor XI deficiency are prone to excessive bleeding after injury or surgery, but the existence of a haemorrhagic tendency in partial factor XI deficiency is controversial. In this study, 172 members of 30 kindreds (20 non-Jewish) transmitting factor XI deficiency in North West England were interviewed and a bleeding history questionnaire completed. Blood was taken for coagulation assays. The questionnaires were categorised independently by two assessors to determine presence or absence of a bleeding tendency, in the absence of information about the factor XI level or family history. Analysis shows that 48% of heterozygotes have a bleeding tendency. Eighteen (60%) families came to attention because of bleeding problems in heterozygotes. Comparison of histories between partially deficient and non-deficient individuals demonstrated a higher incidence of menstrual problems, an increase in significant bruising, and an increased likelihood of excessive bleeding after tonsillectomy and dental extractions. The incidence of von Willebrand's disease was not increased, but individuals with heterozygous factor XI deficiency who were bleeders tended to have lower levels of factor VIIIc and von Willebrand factor, and were more commonly of blood group 0. These features may contribute to the bleeding tendency. There was no evidence of alteration in factor VII activity (as defined by the ratio of activity to antigen) between the bleeders and non-bleeders. This is convincing evidence for abnormal bleeding in factor XI deficiency which is not confined to severely deficient patients.

Adolescent↗