Companies:  Haemonetics

Apheresis (cytapheresis and Plasmapheresis):

Conventional apheresis methods include centrifugation, which can separate any of the components of the blood, and membrane filtration, which can be used for plasmapheresis only. (David M. Ward “Conventional Apheresis Therapees: A REview” J. Clinical Apheresis 26: 230-238 (2011). 

Cytapheresis: incldues teh removal of excessive white blood cells (leukocytopheresis) or platelets (thrombocytapheresis) or the exchange of diseased red blood cells (erythrocytopheresis). 

Plasmapheresis is the separation of whole blood into a plasma componet and a non-plasma component where the plasma component is retained and the non-plasma component is returend to the dornor. A variety of satellit pouch plasmapheresis systems have been patented where whole blood is withdrawn form a donor and flows to a pouch containing anticoagulant. The pourch is then disconnected from the donor phelbotomy line, centrifuged, and the sueprnatant plasma fraction is expressed into a connected plasma pouch. The pouch containing teh non-plasma componetn is then reconnected to the phelbotomy system to be returend to the conor.

Therapeutic plasmapheresis and therapeutic plasma exchange (TPE) are terms that are often used synonymously. The plasma that is removed can be replaced by fresh frozen plasma (FFP), 5% albumin or similar colloidal solution, or the patient’s own plasma after a secondary online purificaotn prcoecdure. Most commonly the objective of plasmapehresis therapy (TPE) is to remove antibodies implicated in the pathogenesis of autoimmune disease. Other important targets include circulating antigen-antibody complexes that cause vasculitis in conditions such as hepatitis C, alloantibodies in transplant rejections and transfusion situations, parapropteins that casue hypervisosity or neurologic and renal damage, pooly characterized pathogenic molcules such as in focal segmental glomerulosclerosis (FSGS), low MW lipoporteins that casue premature atherogenesis in homozygous hypercholesterolemia, and other endogensous and exogenous toxins.  (David M. Ward “Conventional Apheresis Therapees: A REview” J. Clinical Apheresis 26: 230-238 (2011). 

For example, treating rheumatoid arthritis patients by apheresis utilizes an immunosorbent device to remove immune complexes. For example, the Prosorba Column is a single use device that ctonains Protein A covalenty boudn to inert silica granules. When plasma is passed thro the device the immobilized Protein A binds outthe circualting cimmune complexes. The cleaned plasma is then returend to the pateint. Smith (WO 2006/076480)

 Aparatuses/Devices:

Fell (US 5,387,187) disclsoes an aperhesis apparatus for separating blood. A phelbotomy needle draws anticoagulated whole blood from a donor into a seapration chamber that seaprates plasma from higher density blood components. The plasma is displaced to a plasma collection bag. The seapration process is terminated and the higher density blood components remaining in the separation chamber are diluted with saline solution and are returend to the donor via the phelobotomy needle. 

Lathan (US 4,086,924) described an apparatus where whole blood is withdrawn from a donor using a phlebotomy needle and pressure cuff, measns for supplying anticoagulant to the withdrawn blood and the anticoagulated withdawn whole blood is then transported by a blood pump to means for seaprating it into a plasma and a non-;lasma component such as a plasmapheresis centrifuge. 

Extracorporeal Immunoadsorption:

–Specific ligands (e.g., antibodies, Protein A) bound to Support:

In immunoadsorption (IA) a biospecific column can be used for an extracorporeal blood treatment. The IA column contains a material consisting of a matrix having at least one ligand covalently bound thereto. An example of an IA column is a protein A containing column. Otehr examples are immunoglobulin based columns for specific elimination of immunoglobulins from blood plasma. In IA a plasma filter or a contrifuge is used, which continously spearates the plasma from teh blood cells. Then the blood plasma is transported via a tube to a column, in which the target protein or componetn is bound and thereby is specifically separated form other blood plasma components. Nilsson (WO 2013/062479)

Extra-corporeal immunoadsorption (ECI) consists of a highly purified protein A that is bonded to a silica matrix. (see for example Prosorba column). Plasma is collected form the patient in a pheresis procedure and then passed over the column. circulating immune complexes and IgG bind to the protein A and thus selectively removed from plasma. The plasma can then be returend to the pateint, thus eliminating the need for a plasma exchagne. It is useful for treating Idiopathic thrombocytopenic purpura (ITP) which is characterized by rapid platelet destruction and typicallyt appears in young women and also in male patietns who are sero-positive for HIV, hemolytic uremic syndrome (HUS), and it has also benen approved for rheymatoid arthritis (RA). , Germany received FDA approval for pateints with hemophelia devleoping inhibtors, i.e., allo-antibodies directed agaisnt factor cocnetrates. (Bittermann, WO 2014/0201542). 

The molecular interaction between protein A and Ig is well characterized adn the binding site on teh Fc fragment involves residues in the CH2ZCH3 region of particularly IgG1, IgG2, IgG4 and to a lesser extent to IgG3. IA columns approved by the FDA include the protein-A silica column (Prosorba, Fresenius Medical Care, Redmont, CA) for teh treatment of refractory rheumatoid arthritis and for resistant idiopathic thrombocytopenic purpura. The prtoein-A sepharose column Immunosorba, Fresenius Medical Care, St Wendel, Saarland

Jones (US 5,782,792) discloses exposing blood plasma to a protein A immunoadsorbent which binds to IgG containing immune complexes with high affinity and is useful for the treatment of Rheumatoid arthritis).

Nilsson (WO 2013/062479) discloses a method for extracorporeal elimination of one or mroe components from blood which incldues adding whole blood or blood plasma to a blood treatment device such as a blood bag or a blood plasma bag or column containing an adsorbent, consisting of at least one matrix and at least one ligand covalently bound thereto. The antibody, protein or other component bound to the adsorbent may be eluated from the adsorbent as by chaing the pH.  

Palmer (“removal of anti-HLA antibodies by extracorporeal immunoadsorption to enable renal transplantation” 333(8628), 1989, p. 1989, Lancet) discloses that anti-HLA antibodies may occur as a result of failed blood transfusions or pregnancy and that in this respect kidneys have been successfully transplanted after anti-HLA antibodies were removed by extracorporeal immunoadsorption with staphylococcal prtoein A. Since the vast majority of anti-HLA antibodies are IgG, they can be removed by this technique. Plasma was passed through one of the two columns while the other is being regenerated. Treated plasma, depleted of IgG, is returend to the patient. 

Smith (WO 2006/076480) describes targeted apheresis where an immunosorbent apehresis cartridge containing immobilzied human IgG is used to selectively remove immune complexes and RF from the blood Purified IgG can be isoalted form blood used to preapre the apheresis cartidge becasue RF has been shown to react with altered IgG . The altered IgG is immobilzied to a support matrix such as agarose beads.

Removal of Antigens/Pathogens

Ambrus (US4,714,556) discloses an extracorporeal apparatus having hollow fiber UF membranes which have attached proteins having strong affinity for pathogenic factors/antigens in blood.

Removal of Plasma Proteins

Immuno-Affinity columns in series:

Naylor (WO 2004072647) discloses immunoaffinity chromatography coloms and affinity disks configured in series for teh revmoal/depletion of two or more proteins such as HSA, IgG figrinogen, etc. from blood serum, blood plasma, cerebrospinal fluid and/or urine samples. 

Ofsthun (US 5,871,649) discloses an affinity membrane devide for removal of target molecules in plasma. The device is used in an extraceorporeal blood circuit and consists of hollow fiber membranes, ligand immobilized in the pore surface of the hollow fibers and a housing to encase the follow fibers. The plasma components flow into and out of the hollow fiber by means of positive and reverse filtraiton. Initially, as the blood to be treated is transported into the membrane device, the pressure of the blood inside of the hollow fiber causes plasma to pass form the lumen by convention towards the shell of the elongated housing. Then, near the outlet , the pressure inside the hollow fiber membrane is lower than the pressure of the plasma outside of the fiber. As a reslt, the plasma then flows back into the lumen. The plasma that flows back through the wall has been treated or modified with the ligands immobilized to the surface of the pores of the fiber. 

Enzyme coated

Sjoholm (WO0069869) discloses a microporous membrane that includes an immobilized biologically active substance in the form of hollow fibres enclosed within an outer casing with a first inlet and a first outlet. In one embodiment, the biologically active subsance is the enzyme asparaginase from E coli, stabilized on microparticulate polyamide grain enclosed in hollow fibre pores. The enzyme can break down asparagine, which is essential for tumor cells. 

Removal of Antibodies/Immunoglobulins

Leventhal (WO 95/31209) discloses a method for preventing or ameliorating hyperacute rejetion which occurs upon transplant of a pig organ which involves perfusion of the recipient’s plasma over  a coulumn coupled to a protein that binds to human immunoglobulin. The immunoglobulin binding protein can be Staphylococcus aureus protein A/G and anti-human immunoglobulin antibodies. 

Sowemimo-Coker (US 2012/0219633; see also US 15/665971, published as US 2017/0368477; see also US Patent Application 16/090,689, published as US 2020/0325169)) disclsoes a filter device that includes a firt container for receiving biological fluid and containing immunoglobulin binding media and a downstream luekocyte depletion filter. The immunoglobulin binding media can include a variety of functional groups (e.g., ionic, hydrophobic, acidic, basic) such as 4-MEP HyperCell or chromatography osbents with Protein A/G, hydroapatite. 

Removal of Particular Types of Cells

Efficient separations of certain types of cells from complex mixtures has important applications in blood trasnfusions, cancer therapies, auto immune diseases and diagnostics. Cell separation devices employed in these separations have been used in extracorporeal circuits to selectively isolate a specific subset of cells. Separation prcoesses may be used to remove a subset of cells (negative slection). Datar (US 6,008,040)

Leukocytes are present in blood in a wide variety of sizes. For instance, gell like aggregates may be in blood in sizes which vary up to about 200 micrometers. Luekocytes range form macrocytes and granulocytes, typically 15-20 micrometers to lymphocytes which are 5-7 micrometers and large. Datar (US 6,008,040)

Red blood cless are typically 7 micrometers in diameters. Datar (US 6,008,040)

All cells are able to deform as to pass through much msaller openings than their normal size, as in the case of flow in capillary blood vessels. Datar (US 6,008,040)

Leukocytes (white blood cells):

–Negative Selection

Bormann (US 2005/0247627) discloses a file divice for producing a leukocyte depleted plasma rich fluid where the the filter includes a first filter element that includes a porous fibrous leukocyte depletion medium having a first predtermiend critical wetting surfae tension and a second filter elements that includs a porous fibrous leukocyte depletion medium having a second CWST. 

Datar (US 6,008,040) discloses a negative selection of luekocyes by using a continously cascaded toruous flow path. One or more specific ligands may be added to the packings to interact with one or more componetns in the fluid mixture from which the components need searpated. The cascading flow channel provdies a smooth trickling flow of the fluid mixture which porviding increased surface area and decreased hydraulic pore diameters of the separation media, as well as increased interaction between the omponents containin the fluid matrix and the seapration emdia. In one embodiment, a prcoess is provided to simultaneously remove rejection antibodies by using ligands such as emlibiose which are attached to cross-linked, baeded agrose particles and attached to IgM. 

Lee (US 6,337,026) discloses a high capacity luekocyte depletion filtration media that incorporate a high specific surface area components with a matrix of fibers, yielding a filtration medium that remove leukocytes byat least 99.99%. 

Pall (US 4,925,572) discloses a device for the depletion of leukocytes which includes successfive porous elements such that each successive elment has a smaller pore diameter than that preceding it.