Clinical use of factor IX concentrates.
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Biomedical subjects
Publications and source records attributed to C R Rizza.
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The recognition of traumatic splenic rupture in an 11-year-old severely affected haemophilic boy was delayed for over five weeks. Splenectomy was carried out successfully after the demonstration of splenic rupture by an isotope spleen scan. Splenic rupture is difficult to differentiate from more simple causes of retroperitoneal haematomata in haemophiliacs when there is no massive acute peritoneal bleeding, but it may be identified with isotopic spleen scans so long as the possibility of rupture is borne in mind.
A woman with symptoms of prolonged post-traumatic bleeding was found to have a severe defect of factor XI, and was thought to be homozygously affected. Both her parents, who were first cousins, and all her three children, though asymptomatic, showed a moderate defect and appeared to be heterozygous. Both her parents' factor XI levels were about twice those in her children, and this was thought to be an age effect.
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The results of a double-blind controlled trial, previously reported, showed that EACA is a useful adjunct to preoperative therapeutic concentrates of factor VIII or IX for dental extractions in hemophilia and Christmas disease. To estimate the amount of factor VIII and IX conserved in hemophiliacs receiving EACA for dental surgery compared with those not receiving EACA we have surveyed the usage of therapeutic materials in ten hemophilia centers in the U.S. and at Oxford. The amount of postoperative factor-VIII containing materials given to 20 U.S. hemophiliacs not receiving EACA averaged 11 062 units of factor-VIII activity per patient; 4,146 units for each of 22 U.S. patients receiving EACA; and 717 units for each of 56 patients at Oxford receiving EACA. Conservation of factor-IX-containing material was not as great. At Oxford 62.5% of patients receiving preoperative factor-VIII or -IX concentrates sufficient to raise the deficient factor to 50% of normal together with EACA, 24 g per day for ten days, required no postoperative therapeutic materials to control bleeding. The remainder required an average of two postoperative doses to control bleeding.
A new rapid method for assaying total antithrombin activity has been developed based on the inactivation of thrombin incorporated into an agarose gel, during the radial diffusion of plasma in the gel. The area of thrombin inactivation is subsequently observed by the coagulation of fibrinogen in a separate agarose gel layer poured over the thrombin gel. The method is described in detail and its accuracy assessed with respect to other antithrombin assays. Using specific antisera to alpha2-globulin (antithrombin III), alpha2-macroglobin and alpha1-antitrypsin, total antithrombin activity measured by this assay consisted of 47% alpha2-globulin, 29% alpha2-macroglobulin and 26% alpha1-antitrypsin.
A method for detecting factor-VIII clotting activity in agarose is described. It is based on factor VIII promoting coagulation in a mixture of haemophilic plasma in agarose which is detected by a change in opacity. When this test was used to detect factor-VIII clotting activity in a one-dimensional Laurell electroimmunoassay for factor VIII-related antigen all the factor-VIII activity was found in the same position as the factor VIII-related antigen immunoprecipitate. Factor-VIII clotting activity did not appear to be simply trapped in this immunoprecipitate and therefore it has been concluded that the molecule containing factor-VIII clotting activity carries factor VIII-related antigen determinants.
A survey is presented of the use of the Oxford type DE(I) II-IX-X concentrate in the treatment of Christmas disease in Oxford from January 1970 to September 1974. 72 different patients were treated with a total of 2436 bottles of this concentrate from 143 different batches (each bottle containing 800-1000 units of factor IX). Although most doses were given for the treatment of minor haemorrhages into joints and muscles, 717 bottles of concentrate were used to treat 11 patients who underwent 14 major surgical operations. No episode of intravascular clotting or pulmonary embolism was seen in any patient receiving the concentrate. A detailed study of the plasma levels of factor V, VIII, total progressive antithrombin, platelets and fibrinogen degradation products was carried out before and after transfusion of type DE(I) concentrate in 14 patients. No significant alteration in those factors was found after the transfusion.
A 'blind' study has been made to try to find out if it is possible to diagnose carriers of haemophilia. A group of 34 obligatory carriers of haemophilia were compared with 34 normal women. Levels of factor VIII activity, factor VIII-related antigen, factor V and ratio of factor VIII activity to factor VIII-related antigen were measured. In the carrier group the mean level of factor VIII activity and the mean level of the ratio of activity to antigen were each approximately half of those found in the normal women. The mean level of factor V was the same in both groups of women. By setting the lower limit of normal at the lowest level of the different factors found in the normal women, 12 out of 34 (35%) carriers could be distinguished on the basis of their factor VIII level alone; 24 out of 34 (71%) could be detected on the basis of the ratio of factor VIII activity to factor VIII related antigen and 25 out of 34 (73%) could be detected if both factor VIII activity and the ratio were taken into account. It is concluded that consideration of both the level of factor VIII activity and the ratio of factor VIII activity to factor VIII-related antigen is of some value in detecting carriers of haemophilia. The number of carriers detected (73%) in the present study is not as high as that found by other workers.
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To assess the value of clotting factor concentrate infusions in fulminant hepatic failure, a controlled trial was performed in which nine patients were randomly allocated to treatment with either concentrate alone or concentrate plus heparin. The five patients receiving concentrate alone all died, with major bleeding as the direct cause of death in three, whereas in the four receiving heparin as well there was only one instance of bleeding and one patient survived. Clinical evidence of intravascular coagulation appeared in two patients treated with concentrate alone and the laboratory evidence of this progressed during the period of infusions in all patients in both treatment groups, although to a lesser extent in those receiving heparin. Additional evidence for intravascular coagulation came from the changes observed in factor VIII levels which, although initially high in all patients, fell subsequently, particularly in those given concentrate alone. There was some improvement in the prothrombin ratio in both groups of patients but not complete correction, and serial assays of clotting factors showed that although factor II rose to high levels during treatment, factors IX and X showed little response. Thus, the use of concentrate of factor IX in this trial, as well as potentiating intravascular coagulation, was inadequate as replacement for the clotting factor deficiencies.
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