Multiple coagulation factor abnormalities in commercially available Passovoy-deficient plasma.
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Adult↗
Biomedical subjects
P A Foster
Publications and source records attributed to P A Foster.
Problems with the international normalized ratio.
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Humans↗
Fine mapping of monoclonal antibody epitopes on human von Willebrand factor using a recombinant peptide library.
A recombinant human von Willebrand factor (vWF) cDNA fragment library was constructed in lambda gt11 for the localization of anti-vWF monoclonal antibody epitopes. Twelve of 21 monoclonal antibodies screened identified epitopes expressed in lambda gt11 as beta-galactosidase fusion proteins. By sequence analysis, these antigenic determinants were localized to segments ranging from 17 to 105 amino acids in length. Four epitopes apparently shared by more than one antibody were identified, suggesting the presence of immuno-dominant epitopes within vWF. Monoclonal antibody C3, which blocks factor VIII (FVIII) binding to vWF, bound to the same epitope previously identified by a second monoclonal antibody which also blocks this function, suggesting that this region may be at or near the vWF/FVIII binding domain. Three antibodies recognize the same region within the vWF A2 repeat. Mutations near this region appear to be responsible for Type IIA von Willebrand's disease. The co-localization of these antibodies suggests that this domain might be exposed on the surface of vWF, consistent with its apparent increased sensitivity to plasma proteases.
Antibodies, Monoclonal↗
The effect of combined estrogen/progestogen treatment in women with hyperprolactinemic amenorrhea.
Eleven women with hyperprolactinemic amenorrhea were treated with a combined estrogen/progestogen preparation (Loestrin 30) for 3 months as hormone replacement therapy because of estrogen deficiency, with a view to protection against osteoporosis. Serum prolactin levels rose during the 1st month of treatment (p < 0.05) but did not rise significantly further during the 2nd and 3rd months. The levels rose in proportion to pretreatment levels by 28% (median), and fell significantly but not completely during the 1-week treatment-free intervals. After the study period, prolactin values appeared to remain stable in those women who continued longer on treatment, and returned to around pretreatment values in those who stopped. In one woman there was radiological evidence of pituitary tumor growth during treatment. This study shows that estrogen/progestogen treatment in standard contraceptive dosage usually leads to only moderate and non-progressive stimulation of pituitary activity in women with hyperprolactinemic amenorrhea, but occasional excessive growth of a prolactinoma can occur and treatment needs to be monitored. Women with relatively high prolactin levels seem to be at particular risk. Safer variations of estrogen therapy such as lower dosage or combination with a protective low dose of a dopamine agonist should also be considered.
Adolescent↗
A synthetic factor VIII peptide of eight amino acid residues (1677-1684) contains the binding region of an anti-factor VIII antibody which inhibits the binding of factor VIII to von Willebrand factor.
The monoclonal anti-factor VIII (FVIII) antibody C4 has previously been reported to inhibit the binding of purified FVIII to immobilized von Willebrand factor (vWF). The binding area of C4 was identified to be within fifteen amino acid residues (1670-1684) based on the ability of a synthetic FVIII peptide consisting of amino acid residues 1670-1684 to completely inhibit the binding of C4 to FVIII. We now report the further localization of the binding region of C4 to within eight amino acid residues (1677-1684) of FVIII light chain. Nine new overlapping FVIII peptides were synthesized based on the amino acid sequence of the acidic region of FVIII light chain and tested, along with seven previously tested peptides, for the ability to inhibit C4 binding to FVIII in an ELISA assay. Three synthetic FVIII peptides 1670-1684, 1675-1690, and 1677-1684 demonstrated dose dependent inhibition of C4 binding to FVIII. The three reactive peptides contain residues 1677-1684 in common. Since C4 can completely inhibit the binding of FVIII to vWF, this report further localizes an eight amino acid residue region of FVIII which may be important in the mediation of vWF binding.
Amino Acid Sequence↗
Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine.
The effective activation of factor X by factor IXa requires the co-factor activity of activated factor VIII (FVIII). Factor Xa formation is also dependent on the presence of negatively charged phospholipid. A phospholipid binding domain of FVIII has been reported to be present on the FVIII light chain. Recent observations on a subset of human FVIII inhibitors have implicated the carboxyl-terminal C2 domain of FVIII as containing a possible phospholipid binding site. The purpose of this study was to investigate directly the role of the C2 domain in phospholipid binding. Twenty-six overlapping peptides, which span the entire C2 domain of FVIII, were synthesized. The ability of these peptides to inhibit the binding of purified human FVIII to immobilized phosphatidylserine was evaluated in an enzyme-linked immunosorbent assay. Three overlapping synthetic FVIII peptides, 2303-2317, 2305-2332, and 2308-2322, inhibited FVIII binding to phosphatidylserine by greater than 90% when tested at a concentration of 100 mumols/L. A fourth partially overlapping peptide, 2318-2332, inhibited FVIII binding by 65%. These results suggest that the area described by these peptides, residues 2303 to 2332, may play an important role in the mediation of FVIII binding to phospholipid.
Amino Acid Sequence↗
Effect of bladder filling on embryo transfer.
We have investigated a claim that bladder filling, by straightening an anteverted uterus into line with the vagina, might facilitate embryo transfer through the cervix after in vitro fertilization. In a randomized controlled trail in 66 women with and 76 without a filled bladder, we found no significant differences in difficulties encountered at embryo transfer or in the chance of pregnancy.
Adult↗
Factor VIII structure and function.
The relatively recent ability to obtain highly purified factor VIII (FVIII) preparations from plasma products, the cloning of the FVIII gene, and the expression of recombinant FVIII have provided the basis for significant advancements in the understanding of the structure-function relationships of FVIII. Evaluation of the molecular structure of FVIII has revealed the presence of domains of significant internal amino acid sequence homology as well as homology with similar structural domains of factor V. Specific proteolytic cleavage sites have been identified in the molecule and the use of site directed mutagenesis has identified those proteolytic cleavage sites required for the activation of FVIII. Deletion and substitution variants of FVIII as well as the precise epitope mapping of FVIII antibodies which inhibit the procoagulant function of the protein or its binding to von Willebrand factor have provided insight into the identification of regions of FVIII which are required for normal function.
Factor VIII↗
An immunogenic region within residues Val1670-Glu1684 of the factor VIII light chain induces antibodies which inhibit binding of factor VIII to von Willebrand factor.
We have identified a monoclonal anti-factor VIII (FVIII) antibody, C4, which inhibits the binding of purified human FVIII to purified human von Willebrand factor (vWF). Both whole immunoglobulin C4 and its Fab fragment demonstrated dose-dependent inhibition of FVIII binding to vWF immobilized on the surface of polystyrene beads. Synthetic peptides based on the amino acid sequence of FVIII were tested for the ability to block the binding of C4 to FVIII in an enzyme-linked immunosorbent assay system. A single synthetic FVIII pentadecapeptide, consisting of residues Val1670-Glu1684, was able to inhibit C4 binding to FVIII. Under the conditions used, the Val1670-Glu1684 peptide demonstrated total inhibition of C4 binding at a concentration of 1 microM. Synthetic FVIII peptides flanking and overlapping the Val1670-Glu1684 peptide had no significant inhibitory activity on C4 binding in concentrations up to 100 microM. A polyclonal antibody made to the Val1670-Glu1684 peptide also demonstrated inhibition of FVIII binding to vWF. Polyclonal antibodies made to synthetic FVIII peptides flanking and partially overlapping the Val1670-Glu1684 sequence did not demonstrate such inhibition. Localization of the binding region of the monoclonal anti-FVIII antibody C4 to residues Val1670-Glu1684 suggests that this site is at, or near, a major vWF binding domain of FVIII.
Amino Acid Sequence↗
The use of propofol in a group of older patients undergoing oesophagoscopy.
Propofol (Diprivan; Stuart) a new, very short-acting intravenous anaesthetic agent, was tested in its aqueous emulsion formulation. Used as an induction and maintenance agent, its anaesthetic properties, dosage requirements and side-effects were compared with those of thiopentone in 40 American Society of Anesthesiologists class I and II patients scheduled for routine oesophagoscopy. Both heart rate and diastolic blood pressure were more stable in the propofol group, and recovery times were significantly shorter. Patients were remarkably clear-headed after propofol. When the quality of anaesthesia was independently assessed by an anaesthetist and a surgeon, propofol was rated good or satisfactory in all subjects, and thiopentone in 80%. Anaphylactoid reactions associated with the previous Cremophor EL formulation were not encountered, and pain on injection was experienced in 10% of propofol subjects as against 5% who received thiopentone. This new intravenous agent produces safe and predictable anaesthesia followed by rapid recovery, making it especially suitable for outpatient anaesthesia.
Aged↗
Propofol in total intravenous anaesthesia without nitrous oxide.
Propofol and methohexitone were evaluated as hypnotics in a total intravenous anaesthesia technique without nitrous oxide in 50 patients of ASA grade 1 or 2. Analgesia was provided by a constant alfentanil infusion and the depth of anaesthesia was controlled by varying the infusion rate of propofol or methohexitone. Induction and intubation responses were smooth and moderate in the propofol group and side effects were few. Control of depth of anaesthesia, blood pressure and pulse rate was relatively easy in this group but more difficult and sometimes inadequate in the methohexitone group, in which side effects were more frequent. The mean infusion rate for propofol was 0.12 mg/kg/minute, similar to those found in studies using nitrous oxide without an opioid. Recovery times were short in both groups but those in the propofol group tended to be shorter. Postoperatively 96% of the propofol patients were clear-headed within 20 minutes, in contrast to only 48% in the methohexitone group. We conclude that propofol together with alfentanil, both given by a bolus plus infusion technique, provide controllable and satisfactory total intravenous anaesthesia without recourse to nitrous oxide or other inhalational agents. Methohexitone was not as satisfactory as propofol.
Adult↗
Localization of the binding regions of a murine monoclonal anti-factor VIII antibody and a human anti-factor VIII alloantibody, both of which inhibit factor VIII procoagulant activity, to amino acid residues threonine351-serine365 of the factor VIII heavy chain.
We have localized the binding region of a previously described monoclonal anti-factor VIII (FVIII) inhibitory antibody (C5) to amino acid residues Thr351-Ser365 of the thrombin-generated 54-kD fragment of the heavy chain of FVIII. Synthetic FVIII peptides were examined for the ability to competitively inhibit the binding of C5 to FVIII in an ELISA system. The synthetic FVIII peptide Thr351-Ser365 blocked C5 binding to FVIII in a dose-dependent manner in this system. Two other synthetic FVIII peptides, Asn340-Glu354 and Glu342-Asp356, which partially overlapped Thr351-Ser365, also blocked C5 binding to FVIII. Blocking of C5 binding with these peptides, however, required much greater concentrations (greater than 100 times stronger) than that required for Thr351-Ser365. The Thr351-Ser365 peptide also neutralized the FVIII inhibitory activity of C5 in plasma. A human FVIII inhibitor (anti-FVIII heavy chain alloantibody) was also partially neutralized by Thr351-Ser365. Thr351-Ser365 lies between a thrombin cleavage site (Arg372) and an activated protein C cleavage site (Arg336) and may be at or near a region of functional importance in the expression of FVIII procoagulant activity.
Amino Acid Sequence↗
A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor.
We have identified a Factor VIII (FVIII) binding domain residing within the amino-terminal 272 amino acid residues of the mature von Willebrand Factor (vWF) subunit. Two-dimensional crossed immunoelectrophoresis showed direct binding of purified human FVIII to purified human vWF. After proteolytic digestion of vWF with Staphylococcus aureus V8 protease (SP), FVIII binding was seen only with the amino-terminal SP fragment III and not with the carboxyl-terminal SP fragment II. A monoclonal anti-vWF antibody (C3) partially blocked FVIII binding to vWF and SP fragment III. FVIII also bound to vWF which had been adsorbed to polystyrene beads. This binding was inhibited in a dose-dependent manner by whole vWF, SP fragment III, and by monoclonal antibody C3. Binding could not be inhibited by SP fragment I, which contains the middle portion of the vWF molecule, or by reduced and alkylated whole vWF. SP fragment II caused only minimal inhibition. Trypsin cleavage of SP fragment III produced a monomeric 35-kDa fragment containing the amino-terminal 272 amino acid residues of vWF. This fragment reacted with monoclonal antibody C3 and inhibited the binding of FVIII to vWF in a dose-dependent manner. These studies demonstrate that a major FVIII binding site resides within the amino-terminal 272 amino acid residues of vWF.
Amino Acid Sequence↗
Where is the endotracheal tube?
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Humans↗
In vitro fertilization: fertilization failure due to toxic catheters.
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Animals↗
Endometriosis and IVF: effect of prior therapy.
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Endometriosis↗
Norethisterone treatment to control timing of the IVF cycle.
The use of norethisterone to control the timing of the preceding menstrual cycle and in consequence the timing of the in-vitro fertilization (IVF) cycle has been evaluated in a therapeutic IVF programme in which oocyte recovery was limited to 2 days each week. A consecutive series of 181 cycles after norethisterone and 29 untreated controls were compared. Menstruation occurred 2-3 days after norethisterone as planned in 82% of patients overall and in 87% of patients whose menstrual cycle length varied by no more than 2 days about the median. Norethisterone treatment did not significantly affect the outcome of IVF treatment compared with the controls in respect to cycles abandoned (12 versus 0%, respectively), peak follicular diameter (mean 18.1 mm versus 18.3 mm 48 h before laparoscopy), oocyte recovery rate (4.6 versus 4.5 per patient), oocyte morphology (63% versus 52% mature), or fertilization rate (72 versus 65% of mature oocytes). Clinical pregnancies were too few for comparison (rates 27 versus 9% per laparoscopy) but the overall rate (23%) indicated effectiveness of the methods. Prior norethisterone treatment appears to be an effective and useful means of controlling the timing of the oocyte recovery in IVF treatment.
Female↗