Plasmapheresis and Factor VIIIC inhibitors.
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Biomedical subjects
Publications and source records attributed to J F Davidson.
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BRL 26921 is the p- anisoyl derivative of the primary streptokinase-human plasminogen complex in which the acyl group is specifically located at the catalytic centre of the enzyme. Doses of BRL 26921 ranging from 5 mg to 25 mg were given intravenously or into a coronary artery to 12 patients with acute myocardial infarction. The complex was well tolerated and produced no serious bleeding. Coronary artery reperfusion was demonstrated angiographically in three patients. In most patients, fibrinogen, plasminogen, alpha 2 antiplasmin and alpha 2 macroglobulin levels fell and the level of fibrinogen degradation products increased acutely post treatment indicating systemic fibrinolytic activation. The degree of this activation was variable but was profound in some. It appeared to be dose related and modified by the presence of streptokinase antibodies. BRL 26921 appears less "selectively" thrombolytic in patients than had been expected from animal models.
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The performance of a commercially available assay for the determination of prothrombin by a chromogenic substrate method has been evaluated for use on an automated clinical analyser. The method was rapid and simple; accuracy, precision and sensitivity were satisfactory, while carry-over was negligible. Determinations were performed on 170 plasma samples from patients on long-term oral anticoagulant therapy, using the automated amidolytic method; comparison of the prothrombin levels with results obtained by the prothrombin time and Thrombotest methods provided highly significant correlations.
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1 Plasma thromboxane levels were obtained from both the coronary sinus and aorta in patients with stable angina pectoris paced to angina, and in unstable angina patients before and after dazoxiben 100 mg. 2 Although there was a wide range of values in the different groups, dazoxiben significantly reduced plasma thromboxane levels in all patients. 3 Dazoxiben had no adverse effect on coronary and systemic haemodynamics, and atrial pacing time to angina was increased from 245 +/- 41 to 308 +/- 48s (P less than 0.01).
Freeze dried cryoprecipitate was used in the treatment of 14 patients with haemophilia A. The in vivo recovery was 91.2% which is comparable to that reported from other parts of Europe. The product was efficacious and no adverse effects were reported. Freeze dried cryoprecipitate is the high yield product of a low technology process and as such may be of value in reducing any possible shortfall in the factor VIII requirements of the haemophiliac population of the UK.
The effects of prostacyclin (PGI2) on postoperative blood loss and on the deposits which are known to form on filters in the bypass circuit were studied in patients undergoing operations with cardioopulmonary bypass. In this double-blind, randomized study, PGI2 or a placebo solution was administered to 56 patients undergoing elective cardiac operations. At the end of cardipulmonary bypass, the arterial line filter was removed from the circuit and blood losses were accurately recorded. There was no statistically significant difference in either the amount or the pattern of postbypass bleeding between the PGI2 and the control patients. However, the changes in weight of the arterial line filters and their electron microscopic appearances suggest that PGI2 can reduce the deposition of platelets and fibrin on the filter mesh, and in this role it may be of value in reducing visceral injury during cardiac operations.
An amidolytic assay of factor X based on the new chromogenic peptide substrate S 2337 (Kabi Diagnostica) was adapted for use with the Kem-o-Mat (Coulter Electronics) automated substrate analyser. Factor X was assayed in 25 healthy controls and in 375 patients on Warfarin therapy. The results in the control group correlated well with a one stage coagulation factor X assay. A good correlation was also found when the S 2337 factor X assay was compared with Thrombotest (Nyegaard & Co.) results in the patients. From the regression line of the S 2337 factor X assay on the Thrombotest results, the comparable range for factor X amidolytic activity in well controlled anticoagulated patients was found to be 22.5-37.5% with this method. Concordant classification of patients by both tests according to proposed therapeutic ranges demonstrated fully concordant information in 76% and fully discordant information in none. This study demonstrates that chromogenic substrate assays for anticoagulant control can be readily automated. Amidolytic assays of factor X based on the S 2337 substrate, therefore, warrant further clinical investigation as a potential method for controlling maintenance oral anticoagulant therapy.
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An immuno-affinity chromatography methods was used to isolated human factor VIII and its antibodies and the mechanism of the affinity system was investigated using iodine labelling. Rabbit antibodies to human factor VIII were insolubilised onto CNBr - activated Sepharose 2B which was used for the preparation of affinity columns. Both VIII:C and VIIIR:Ag were adsorbed onto such columns from factor VIII preparations. The subsequent application of immunoglobulin preparations containing human antibodies to factor VIII resulted in the adsorption of these antibodies onto the columns. Adsorbed material was eluted from the affinity columns with 0.2 M glycine - HCl, pH 2.3. When 125I-labelled factor VIII and 131I-labelled human antibodies to factor VII were used in this affinity system, the eluted material could be separated into three fractions by gel filtration on Bio-Gel A 1.5 m. Fraction 1 occurred at the void volume position, fraction 3 at a position corresponding to the elution position of IgG and fraction 2 at an intermediate position. 131I-labelled material was present in all three peaks. 125I-labelled material was present mainly in peak 1, with a little in peak 2. The results support the view that VIIIR:Ag, which binds heterologous antibodies, is non-covalently linked to a smaller subunit, VIII:C, which binds homologous antibodies.
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Nine human antibodies to factor VIII were isolated from haemophilic plasmas by affinity chromatography and gel filtration and six were subsequently subjected to immunological characterization. Three partially purified preparations were similarly characterized. Eight of the antibodies were characterized as being exclusively IgG and one preparation was found to contain IgM. Seven of the antibodies contained only a single light chain type, four being of type lambda and three of type kappa. Two antibody preparations contained both kappa and lambda light chains. In four of the preparations, only a single heavy chain sub-class could be demonstrated, three of IgG3 and one of IgG4. Of the remainder, three were a mixture of IgG3 and IgG4 sub-classes and one contained both IgG2 and IgG4. IgG sub-classification could not be achieved with the IgM-containing preparation. These results demonstrate a restricted heterogeneity of light and heavy chains in human antibodies to factor VIII.
In a double-blind placebo-controlled trial of 48 patients requiring open heart surgery, prostacyclin (PGI2) was infused in a dose of 20 ng/kg/min throughout cardiopulmonary bypass. When compared with the placebo group, the patients given active PGI2 were found to have significantly higher platelet counts from 30 min after commencement of bypass and in the immediate post-operative period, and to have significantly less elevation of the platelet secretory proteins, beta thromboglobulin and platelet factor 4 during bypass. The mean weight increase in the arterial line filters was significantly greater in the placebo-treated patients than in the PGI2 group. It is suggested that infused PGI2 decreases platelet activation during cardiopulmonary bypass and that further studies are required to establish its clinical value in this situation.
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