Clinical Investigation of Intermediate‐ and High‐Purity Antihaemophilic Factor (Factor VIII) Concentrates

Johnson, Alan J.; Karpatkin, Margaret; Newman, Jack

doi:10.1111/j.1365-2141.1971.tb03414.x

Cited by 80 publications

(41 citation statements)

References 31 publications

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“…and injected intramuscularly into chim panzees according to the protocol in table I. The PEG concentration in the final ISG and PPF products was less than 0.1% as determined by assay [15]. Most of the fibrinogen was eluted from the PE resin used for the first adsorption with 0.15 M NaCl at pH 5.5, and the PPF (97% albumin) was eluted at pH 4.0 with 2,500 ml of distilled water at a protein concentration of 10 mg/ml ( fig.…”

Section: Controls0mentioning

confidence: 99%

Freedom from Transmission of Hepatitis-B of Gamma-Globulin and Heat-Inactivated Plasma Protein Fraction Prepared from Contaminated Human Plasma by Fractionation with Solid-Phase Polyelectrolytes

Harris¹,

Johnson²,

Semar³

et al. 1979

Vox Sanguinis

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Plasma contaminated with hepatitis B surface antigen (HBsAg) and shown by others to be infectious when injected in a dilution of 1:1,000,000 in chimpanzees, was fractionated by a solid-phase polyelectrolyte (PE) procedure for its content of plasma protein fraction (PPF) and γ-globulin (immune serum globulin; ISG). Quantitative Ausria II radioimmunoassays showed that nearly half the HBsAg was bound by the PE and could be eluted at low pH, while the rest was found in the heat-inactivated PPF. When the ISG was concentrated to 16%, the 13 mg/kg (comparable to a human dose) was injected intramuscularly in 6 chimpanzees, or when the PPF was heated at 60°C for 10 h and injected intravenously in 2 chimpanzees, there was no clinical or laboratory evidence of hepatitis B infection after 12 months, although 1 chimp of 2 who received the same material showed a borderline positive anti-HBsAg antibody result on one of 52 weekly serum samples. Since the new PE fractionation method is essentially nondenaturing, and simpler than the classical ethanol procedures, it was important to establish the noninfectivity of the final products.

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Section: Controls0mentioning

confidence: 99%

Freedom from Transmission of Hepatitis-B of Gamma-Globulin and Heat-Inactivated Plasma Protein Fraction Prepared from Contaminated Human Plasma by Fractionation with Solid-Phase Polyelectrolytes

Harris¹,

Johnson²,

Semar³

et al. 1979

Vox Sanguinis

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“…The relationship between the HAA positivity obtained by the radio immunoassay and infectivity is yet to be established. Although a low incidence of hepatitis has been reported with the use of factor VIII concentrates derived from unscreened donors [10], it is expected that improvement in the sensitivity of the existing HAA-screening techniques will further reduce, and eventually eradicate, the risk of transmitting hepatitis through the administra tion of factor VIII concentrate.…”

Section: Discussionmentioning

confidence: 99%

“…Such preparations, however, result in a very low factor VIII yield particularly when they are produced on a large scale. Since less purified preparations have shown to be adequate for the treatment of factor VIII deficiency in the vast majority of clinical situations [10] and can be prepared at about twice the yield compared to that of the high-purity material [12], intermediate-purity factor VIII represents a more economical utilization of the presently available plasma resources.…”

Section: Discussionmentioning

confidence: 99%

“…The preparation offactor Vili concentrate involved the following steps: (a) formation of cryoprecipitate in the presence or absence of 3% alcohol by thawing frozen plasma at 0 °C in a water bath or jacketed container heated to 30 °C ; (b) collection of this cryoprecipi tate at 0°C by centrifugation in a discontinuous-type centrifuge (Sorvall, Model RC-3) for small plasma volumes or in a continuous-flow type centrifuge (Sharpies, Model 16) for plasma volumes of 10 Adjustment of pH was carried out with 0.1 n HC1 or 0.1 n NaOH.…”

Section: Methodsmentioning

confidence: 99%

“…Considerable effort, therefore, has been made during the past several years to eliminate some of the disadvan tages of the single-unit cryoprecipitate by providing a standardized, uniform, and stable factor VIII concentrate. The methods which have emerged from these studies have either not been fully disclosed [4], or have been unsuccess ful in providing products which could be sterilized by membrane filtration [9], A method based on extraction of cryoethanol precipitate with tris-HCl buffer, followed by the removal of prothrombin with Al(OH)3 [12], has provided an intermediate-purity AHF which is clinically very effective [10]. However, this method was developed only on a pilot-plant scale (40 1) and attempts to reproduce it on a large scale have frequently failed to provide a concentrate which would meet the minimum requirements of the Division of Biologies Standards of the National Institutes of Health (DBS) [7] in terms of potency and purity [3] or which comprised the yields reported in the original paper [12].…”

Section: Introductionmentioning

confidence: 99%

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Development of Large-Scale Fractionation Methods

James¹,

Wickerhauser²

1972

Vox Sanguinis

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A modification of the method of Johnson for the preparation of clinical factor VIII concentrates is described by which a concentrate may consistently be obtained from 100-liter plasma volumes at a potency of 10 factor VIII units/ml or greater and a specific activity of 0.3 factor VIII units/mg protein (18 to 20-fold purification over plasma) with a final recovery close to 40% of the actual factor VIII activity of the starting plasma; these potency and purity values exceed the minimum requirements of the Division of Biologies Standards of the National Institutes of Health. The major changes that were introduced were: (a) an accelerated cryoprecipitation step to minimize the risk of pyrogen formation; (b) the elimination of ethanol to avoid coprecipitation of nonspecific proteins, thereby improving the purity of the final concentrate; (c) the reduction of the tris extraction volume to obtain a higher final factor VIII potency and smaller volumes for lyophilization; (d) the control of pH during the Al (0H)3 adsorption step to improve the purity and filtrability of the concentrate; (e) the removal of the Al (OH)(3) precipitate by a foamless centrifugation technique to minimize dénaturation of the factor VIII in the supernatant ; and (f ) the use of new clarification media to facilitate the final sterile filtration step.

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Saphenous Vein Arteriovenous Fistulas

Ries¹

1973

JAMA

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analysis of all our phlebotomytreated patients to determine the du¬ ration of induced remissions was made. Follow-up data were available from 24 patients (Fig 3). At one year after attainment of a marked remis¬ sion, all of the 23 patients tested con¬ tinued to be in remission, and at two years all of the 16 patients, including one who had not been tested at one year, demonstrated sustained remis¬ sions. At three years or more, all of the seven patients tested had normal or near normal values. CommentTwo possible mechanisms to ex¬ plain the response to phlebotomy in PCT have been offered: the removal of iron per se, or the removal of a plasma factor. Our studies provide evidence favoring the former. A marked reduction of uroporphyrin ex¬ cretion followed removal of packed RBC only (erythropheresis) in six pa¬ tients with PCT. Moreover, a bio¬ chemical exacerbation followed the administration of iron in two patients in remission that had been induced by previous phlebotomy. Recently Lundvall" reported biochemical relapses oc¬ curring after prolonged oral adminis¬ tration of iron in four patients and after intravenous administration of iron in one patient with PCT. Our data regarding the duration of phlebotomy-induced remissions sup-ports the conclusion that the inter¬ ruption of the biochemical remission following the administration of iron is not a coincidental event.Depletion of total body iron stores involves the plasma as well as the he¬ patic compartments. However, only alterations of the hepatic iron stores seem to be relevant to the develop¬ ment of PCT. For example, we found hepatic siderosis, even of a mild de¬ gree, to be three times more common than hypersideremia. Moreover, se¬ rum iron concentration becomes nor¬ mal during the course of a sustained remission and need not be markedly elevated when a biochemical relapse occurs after the administration of iron.Although it seems clear that he¬ patic iron plays a critical role in porphyrin metabolism in PCT, the exact mechanism involved is not known.One might speculate about two possi¬ bilities. First, iron may in some man¬ ner cause an increase in the hepatic oxidation of the octa-through tetracarboxyl porphyrinogens to their re¬ spective porphyrins. Second, iron might cause a slight, but immea¬ surable, increase in hepatic delta-amino levulinic acid-synthetase7 resulting in increased porphyrin syn¬ thesis, without accumulation of porphyrin precursors because of the lack of an associated block in the heme biosynthetic pathway. Whatever the cause for increased porphyrin synthesis in PCT, iron it¬ self cannot be the sole factor in¬ volved. Alteration of uroporphyrin metabolism is an unusual complica¬ tion of classic hemochromatosis, alco¬ holic hepatic siderosis, or other iron storage diseases. It seems reasonable to conclude that in PCT there is an underlying metabolic defect, perhaps genetically determined, which re¬ quires the participation of certain ac¬ quired factors to result in excessive hepatic porphyrin synthesis. One of these acquired, extrinsic...

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Clinical Investigation of Intermediate‐ and High‐Purity Antihaemophilic Factor (Factor VIII) Concentrates

Cited by 80 publications

References 31 publications

Freedom from Transmission of Hepatitis-B of Gamma-Globulin and Heat-Inactivated Plasma Protein Fraction Prepared from Contaminated Human Plasma by Fractionation with Solid-Phase Polyelectrolytes

Freedom from Transmission of Hepatitis-B of Gamma-Globulin and Heat-Inactivated Plasma Protein Fraction Prepared from Contaminated Human Plasma by Fractionation with Solid-Phase Polyelectrolytes

Development of Large-Scale Fractionation Methods

Saphenous Vein Arteriovenous Fistulas

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