The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action

Blood coagulation is initiated when plasma factor VII(a) binds to its essential cofactor tissue factor (TF) and proteolytically activates factors X and IX. Progressive inhibition of TF activity occurs upon its addition to plasma. This process is reversible and requires the presence of VII(a), catalytically active Xa, Ca2+, and another component that appears to be associated with the lipoproteins in plasma, a lipoprotein-associated coagulation inhibitor (LACI). A protein, LACI(HG2), possessing the same inhibitory properties as LACI, has recently been isolated from the conditioned media of cultured human liver cells (HepG2). Rabbit antisera raised against a synthetic peptide based on the N-terminal sequence of LACI(HG2) and purified IgG from a rabbit immunized with intact LACI(HG2) inhibit the LACI activity in human serum. In a reaction mixture containing VIIa, Xa, Ca2+, and purified LACI(HG2), the apparent half-life (t1/2) for TF activity was 20 seconds. The presence of heparin accelerated the initial rate of inhibition threefold. Antithrombin III alpha alone had no effect, but antithrombin III alpha with heparin abrogated the TF inhibition. LACI(HG2) also inhibited Xa with an apparent t1/2 of 50 seconds. Heparin enhanced the rate of Xa inhibition 2.5-fold, whereas phospholipids and Ca2+ slowed the reaction 2.5-fold. Xa inhibition was demonstrable with both chromogenic substrate (S-2222) and bioassays, but no complex between Xa and LACI(HG2) could be visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Nondenaturing PAGE, however, showed that LACI(HG2) bound to Xa but not to X or Xa inactivated by diisopropyl fluorophosphate. Thus, LACI(HG2) appears to bind to Xa at or near its active site. Bovine factor Xa lacking its gamma-carboxyglutamic acid-containing domain, BXa(-GD), through treatment with alpha-chymotrypsin, was used to further investigate the Xa requirement for VIIa/TF inhibition by LACI(HG2). LACI(HG2) bound to BXa(-GD) and inhibited its catalytic activity against a small molecular substrate (Spectrozyme Xa), though at a rate approximately sevenfold slower than native BXa. Preincubation of LACI(HG2) with saturating concentrations of BXa(-GD) markedly retarded the subsequent inhibition of BXa. The VII(a)/TF complex was not inhibited by LACI(HG2) in the presence of BXa(-GD), and further, preincubation of LACI(HG2) with BXa(-GD) slowed the inhibition of VIIa/TF after the addition of native Xa. The results are consistent with the hypothesis that inhibition of VII(a)/TF involves the formation of a VIIa-TF-XA-LACI complex that requires the GD of XA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Visual impairment in severe and profound sensorineural deafness

The frequency of reversible and irreversible visual impairment was determined in children with severe and profound sensorineural deafness, as subnormal vision can adversely affect their educational and social development. Eighty three of 87 such children attending an audiology service were examined to assess the incidence and severity of visual impairment. Each child underwent a detailed ophthalmic assessment. The criteria for visual impairment were visual acuity < 6/9 Snellen or equivalent and/or abnormal binocular vision. Forty five had a normal ophthalmic examination (54.2%). Twenty nine had visual impairment (34.9%) and nine had ophthalmological abnormalities that did not interfere with vision (10.9%). A higher proportion of children with risk factors for visual pathology demonstrated visual impairment than those in whom there were no risk factors. None the less, 44% of visual impairment was among patients without risk factors. The results underline the need to examine all children with severe and profound sensorineural deafness soon after diagnosis and indicate that children with multiple handicaps have a greater likelihood of visual impairment (11 of 14 cases).     

颅内动脉瘤栓塞后并发脑缺血的原因分析

1 临床资料我们总结2004-02/2004-06在第四军医大学唐都医院神经外科住院行栓塞治疗颅内动脉瘤患者27(男12,女15)例,年龄32～72岁.     

Logarithmic quantitation model using serum ferritin to estimate iron overload in secondary haemochromatosis

Nineteen children and adolescents receiving repeated transfusions and subcutaneous desferrioxamine treatment were investigated in an attempt to quantitate iron overload non-invasively. Before patients were started on desferrioxamine individual relationships were correlated for 12 to 36 months between transfused iron, absorbed iron estimated gastrointestinally, and increasing serum ferritin concentrations. Patients with inflammation, increased liver enzymes, or haemolysis were excluded from analysis. The relationship between the variables could be described by a logarithmic regression curve (y = transfused iron [plus eventually gastrointestinally absorbed iron] = iron overload = a+b log [x = serum ferritin]) for each individual patient. All patients showed close correlation (R2) between x and y (median R2 of 0.909, 0.98, and 0.92 in thalassaemia, aplastic anaemia, and sickle cell anaemia patients, respectively). When started on desferrioxamine, current serum ferritin concentrations were used to derive the iron overload from each individual regression curve. The derived estimated iron overload ranged from 0.6 g to 31 g. Left ventricular dilatation was observed in three patients with beta thalassaemia and in one patient with aplastic anaemia with median iron overload of 20.7 (14.1-31.3) g and 24.0 g respectively. Hypothyroidism was found in four patients with beta thalassaemia and one patient with aplastic anaemia with iron overload between 14.7 (6.8 and 26.1) g and 15.1 g respectively. Human growth hormone deficiency was detected in three patients with beta thalassaemia with an iron overload of 4.2 (3.5-6.8) g; all three patients had excellent desferrioxamine compliance.     

Aortic aneurysm complicating bacterial endocarditis in childhood

Bacterial endocarditis is an uncommon diagnosis in childhood with significant morbidity and mortality. Aortic aneurysm as a complication is well described in adults but there are few reports in the paediatric literature. Two children with bacterial endocarditis are described, whose illnesses were complicated by aortic aneurysm formation requiring surgical intervention.     

Cardiac rhabdomyomas and their association with tuberous sclerosis

A search for children presenting with signs or symptoms of cardiac rhabdomyomas was made through members of the paediatric section of the British Cardiac Society in order to establish their birth incidence, presenting features, clinical course, and the frequency of a concurrent diagnosis of tuberous sclerosis. Fifteen children were identified and 12 had tuberous sclerosis (80%). Heart failure was the presentation in six, five of whom died; six presented because of a murmur and three because of arrhythmias. The prevalence of echocardiographic evidence of cardiac rhabdomyomas in a population of patients with tuberous sclerosis was established. Twenty individuals had echocardiography and eight had echodensities consistent with cardiac rhabdomyomas. It is concluded that the minimum birth incidence for children presenting because of the effects of cardiac rhabdomyomas is 1/326,000 and a minimum of 80% have tuberous sclerosis. In a population of patients with tuberous sclerosis a minimum of 60% under 18 years have cardiac rhabdomyomas.     

Fructosamine and glycated haemoglobin in the assessment of long term glycaemic control in diabetes

Fructosamine and glycated haemoglobin were measured simultaneously in 147 children with diabetes. If glycated haemoglobin is considered as the 'gold standard' for long term glycaemic control, then fructosamine is a poor indicator of actual glycated haemoglobin values, with wide 95% confidence (fiducial) limits. This shows that it is impossible to accurately predict glycated haemoglobin concentrations and therefore, by implication, longer term glycaemic control, from measurements of fructosamine. As the major studies on the prevention of microvascular complications in diabetes have used glycated haemoglobin levels to assess glycaemic control, it is suggested that this measurement should be used in all children with diabetes in preference to the measurement of fructosamine.     

Natural history of trisomy 13

The poor prognosis of patients with trisomy 13 has long been accepted and has been ascribed to brain and heart malformations. It has been suggested, however, that the long term survival is better than was previously thought and that cardiac surgery may be justified. This population based study reviews the incidence, antenatal diagnosis, spectrum of survival from congenital heart disease, and mode of death for patients with trisomy 13 in the Northern Health Region from 1985 to 1992. There was an observed prevalence at birth of 0.049/1000 live births and an expected prevalence, allowing for antenatal diagnosis, of 0.077. None of the cardiac lesions found would cause early death. The median survival in this series was four days; the longest survival was 3.5 months. The principal mode of death was apnoea in 14 of 16 children, irrespective of the presence of a cranial abnormality. In the light of these findings, cardiac surgery cannot be justified in patients with trisomy 13.