Condie, (US 3,998,946) teaches treating blood plasma products with fumed colloidal silica to remove fibrinogen and plasminogen. According to the procedure, blood is centrifuged to separate out the precipitate, the supernantant (plasma) is then centrifuged again and then the supernatant is treated with dry silicon dioxide to separate out the precipitate. The procedure offers the advantage over the classic Cohn alcohol fractionation procedure where plasminogen is concentrated and freed of its inhibitors resulting in greater quantities of plasminogen than are present initially in plasma which can lead to the degradation of fibrinogen to form toxic split products and can also lead to degradation of immunoglobulins (column 2, lines 44-54). Condi (4,296,027, issued 10/20/1981) also teaches plasma stabilization by treatment with fumed colloidal silica.

Condi (US 4136.094) also teaches isolation of IgG for intravenous administration and albumin from plasma by initial stabilization of plasma by treatment with silica. IgG and albumin are then isolated form the stabilized plasma by chromatography.

Bertolini (US 6,093,324) teaches a method for the purification of immunoglobulins from plasma which includes a pretreatment step with finely divided silicon dioxide in order to remove lipoproteins (column 3, lines 49-65). Bertolini teaches that Fraction II+III is already lipoprotein depleted at this point which would obviate the need for application of silicon dioxide and that such a starting material can thus simply be passed through the anion exchange resin (column 6, lines 1-8).

Hirao (US 6159,471) discloses an immunoglobulin preparation formed by treating an immunoglobulin containing fraction with a low concentraiton of PREG, (b) concentrating at acidic pH, (c) anion exchange (e) filtration, (e) treatment with colloidal silica such as silica gel, light silicic anhydride, diatomaceous earth, acid clay, bentonite, kaolin and magnesium silicate aluminate which reduces the amount of serum albumin.

Radowitz (US 4,216,205, IDS Ref. of 10/16/2012) teaches that it was known for the removal of lipoproteins to apply colloidal silicic acid to the serum.

ETOH and Silicon Dioxide

Stephan (US 4,318,902) teaches preparation of an immunoglobulin solution containing IgM comprising treating an IgM containing fraction obtained by conventional fractionation from blood plasma. Advantageously, the IgM containing protein fraction is freed of lipids by treatment with colloidal silica gel (abstract). Stephan exemplifies application of the on Cohn fraction III of human plasma to free lipids (see example 2 of Stephan) (see Buchacher, Biotechnol. J. 2006, 1, 148-163 for a scheme of plasma fractionation according to Oncley’s separation method 9).

Teschner (US2010/0330071) teaches a method for preparing concentrated IgG from plasma by (1) separating liuqid and precipitate from plasma by centrifugation; (2) mixing pre-cooled ethanol with the liquid from (1) to form a mixture, (3) separating liquid and cprecipitate from the mixture of (2) by centrifugation; (4) adjusting pH and ethaol concentration of the liquid from (3) to about 7.0 and 20-25% respectively, thereboy forming a mixture, (5) separating liquid and cprecipitate form the mixture of (4) by centrifugation; (5) resuspending the precipitate of (5) with a buffer, (7) mixing silicon dioxide (SiO2) with the suspension from (6) and obtaining a filtrate by filtration, (8) mixing a detergent and cold alcohol with the filtrate of (7) and obtaing a precipitate by centrifugation, (9) dissovling the precipitate in an aqueous solution comprising a solvent or detergent and maintaining the solution for at least 60 minutes, (10) passing the solution after (9) through a cation exchange column and eluting proteins absorbed on the column in an eluate, (11) passing the eluate form (1) through an anion exchange chromatography column to generate an effluent, (12) passing the effluent through a nanofilter to generate a nanofiltrate, (13) passing the nanofiltrate through an ultrafiltration membrane to generate an ultrafiltrate, (14) diafiltrating the ultrafiltrat.

Teschner also teaches a methdo for reducing the amount of a serine proteasesuch as Factor IIa, Factor XIIa, Factor XI, Factor XII  in a plasma derived target protein (e.g., Factor H, IaI, composition by (a) enriching a plasma derived target protein in a first target protein enricnemnt step comprising alcohol fractionation of a Cohn pool, thereby forming a first enriched plasma derived target protein composition (b) contacting the first enriched plasma derived target protein with finely divided silicon dioxide (SiO2) under conditions suitable to bind at least one serine protease, the conditions comprising a conductivity of from 0.1 mS/cm to 3.0 mS/cm and a PH 4-7.

Silicon Dioxide + Salts

Zurlo (US 17/225,934, published as US 2021/0317163) discloses adding silica granules or poweder to a blood product with an organic salt such as citrate or acetate salt, resulting in precipitate and supernatant fractions. The supernatant fraction can be applied directly to a chromatogrpahic separation step. In a separate embodiment, the blood product is contacted with an organic salt at a first concentration which is sufficient to precipitate non-protein of interest for example from about 5-10% by weight to product a first precipitate which can include the non-prtoein of interest and a first supernatant followed by adding a finely divided silica (e.g., fumed silica) and an additional amount of the organic salt to the frist supernatant to procide a second concentration of the organic salt. This generates a second preciptiate which includes protein of interest such as IgG and the finely divided silica and a second sueprnatant which can include non-protein of intrest. The second preciptiate is resuspended and dissolved which can be applied to a separation column and the IgG containing fraction is collected. 

For inactivation of coagulation factors: 

Kaar (US 2018/0118812) discloses that contacting a solution such as a Fraction I+II+III from plasma fractionation or comparable fractions containing a complex mixture of coagulation factors such as factors VII, FVII, FVIIa, FIX, FIXa, FX, FXI and FXIa with an organic acid or its salt, in particular the sodium salt, inactivated or removed said coagulation factors . It was additionally observed that factor XI-antigen values were reduced to below 5 mlU/mg IgG, when the solution was contacted with caprylic acid  ot its salt. A filtraiton aid such as silicates such as diatomaceous earth, fumed silica, perlites or zeolithes may optionally be present during the stirring and removed together with devleping precipitate afte the contacting. The supernatant can be further processed as by anion chromatogrpahy.