Factor IX concentrates

Affinity chromatography is used in the preparation of more highly purified Factor IX concentrates (53—55) as well as in the preparation of products such as antithrombin III [9000-94-6] (56,57). Heparin [9005-49-6], a sulfated polysaccharide (58), is the ligand used most commonly in these appHcations because it possesses specific binding sites for a number of plasma proteins (59,60). 

Table 11. Properties of Factor VIII (Antihemophilic Factor) and Factor IX Concentrates...

Factor IX Replacement Hemophilia B therapy may include recombinant (produced via transfection of mammalian cells with the human factor IX gene) or plasma-derived (concentrate from pooled plasma) factor IX (see Table 64-2). Guidelines for choosing the factor-concentrate formulation for hemophilia B are similar to the guidelines for hemophilia A. However, older-generation factor IX concentrates containing other vitamin K-dependent proteins (e.g., factors II, VII, and IX), called prothrombin complex concentrates (PCCs), have been associated with thrombogenic side effects. Consequently, these products are not first-line treatment for hemophilia B.11... 

Factor IX concentrates AlphaNine SD domain deleted Plasma Solvent detergent, filtered Heparin... 

Factor VIII process, 12 143 Factor IX, 4 86-87 Factor IXa, 4 86-87, 89 Factor IXa inhibitors, 4 103 Factor IX concentrates, properties of, 72 152t... 

Management is the same as that outlined above but replacement is with fresh frozen plasma or freeze-dried factor IX concentrate. A wide range of commercial equivalents can be used but are costly. 

II Prothrombin deficiency 30-40% 3 days Prothrombin complex concentrates (intermediate purity factor IX concentrates)... 

Smales CM, Pepper DS, James DC (2002), Protein modification during anti-viral heat-treatment bioprocessing of factor VIII concentrates, factor IX concentrates, and model proteins in the presence of sucrose, Biotechnol. Bioeng. 77 37-48. 

Primary prophylaxis with factor VIII three times weekly or factor IX concentrate twice weekly at doses to keep the factor level above 1-2% beginning in toddlers (through an indwelling venous cannula) results in a significant reduction in spontaneous bleeds and arthropathy. 

Parqnet A, Laurian Y, Rothschild C, Navarro R, Gnerois C, Gay V, Durin A, Peynet J, Snltan Y. Incidence of factor IX inhibitor development in severe haemophilia B patients treated with only one brand of high pnrity plasma derived factor IX concentrate. Thromb Haemost 1999 82(4) 1247-9. 

Schulman S, Wallensten R, White B, Smith OP. Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery. Haemophilia 1999 5(2) 96-100. 

During treatment with extremely high doses of factor IX concentrate, to induce immune tolerance, nephrotic sjm-drome has been described (6,7). Withdrawal or dosage reduction is of crucial importance for the resolution of nephrosis (6). Renal biopsy in one of these patients showed peripheral capUlary wall thickening and deposits throughout the basement membrane (7). In addition minimal interstitial fibrosis and tubular atrophy were present. There were no deposits of factor IX in the glomeruli, which the authors attributed to absence of free factor IX epitope in the tissue (7). 

Inhibitors of factor VIII are the most common and develop in 5-15% of patients with hemophilia A. Inhibitors of factor IX develop in 1 % of patients with hemophilia B (11,12). Patients with hemophiha B with complete gene deletions or derangement of the factor IX gene are particularly at risk of developing antibodies after the administration of factor IX concentrate (8). In patients with hemophilia B with antibodies, treatment with factor IX concentrate can result in an anaphylactic response. 

First marketed in the United States in 1996,recombinant factor IX is produced in Chinese hamster ovary cells transfected with the factor IX gene. Blood and plasma products are not used to produce recombinant factor IX nor to stabilize the final product thus recombinant factor IX has an excellent viral safety profile. Clinical trials have shown the product to be safe and efficacious in the treatment of acute bleeding episodes and in the management of bleeding associated with surgical procedures. Although the half-life of recombinant factor IX is similar to that of the plasma-derived products, recovery is approximately 28% lower. As a result, doses of recombinant factor IX concentrate must be higher than those of plasma-derived products to achieve equivalent plasma levels. Because individual pharmacokinetics may vary, recovery and survival studies should be performed to determine optimal treatment. Recombinant factor IX is often considered the treatment of choice for hemophilia B. 

Before the high-purity products were approved for use, hemophilia B patients had been treated with factor IX concentrates that also contained other vitamin K-dependent proteins (factors II, VII, and X), known as prothrombin complex concentrates (PCCs). These products contain small amounts of activated factors generated during processing, and their use has been associated with thrombotic... 

Factor IX is a relatively small protein. Unlike factor VIII, it is not limited to the intravascular space, but also passes into the extravas-cular compartment. This results in a volume of distribution that is approximately twice that of factor VIII. In general, for plasma-derived factor IX concentrates, each unit of factor IX infused per kilogram of body weight yields a 1% rise in the plasma level of factor IX (range, 0.67% to 1.28%). The following equation can be used to calculate the initial dose ... 

Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 2001 98 3600-3606. 

Shapiro AD, Ragni MV, Lusher JM, et al. Safety and efficacy of monoclonal antibody pmified factor IX concentrate in previously untreated patients with hemophilia B. Thrombo Haemost 1996 75 30-35. 

FACTOR IX CONCENTRATES (AlphaNine SO powder for injection, dried plasma fraction of Factor IX, BeneFix powder for injection, nonpyrogenic lyophilized, purified protein produced by recombinant DNA, Monorune powder for injection lyophilized concentrate of Factor IX, plasma-derived, Profilnine SD powder for injection, lyophilized concentrate of Factor IX, plasma-derived, Proplex T powder for injection, plasma derived concentrate of clotting Factors II, VH, IX, and X, Bebulin VH powder for injection, purified freeze-dried concentrate of coagulation Factor IX, II, X, and VII (low amounts), heat-treated)... 

Feldman P.A., Bradbury P.I., Williams J.D., Sims G.E., Mcphee J.W., Pinnell M.A., Harris L., Crombie G.I. and Evans D.R. 1994. Large-scale preparation and biochemical characterization of a new high purity factor IX concentrate prepared by metal chelate affinity chromatography. Blood Coagul. Fibrin., 5, 939. 

Excessive factor IX activity in vulnerable arterial beds, for example atherosclerotic vessels, could lead to thrombotic events, such as venous thrombosis or myocardial infarction. In patients with hemophilia B and cardiovascular disease, factor IX concentrates should be administered slowly or the dose should be reduced [70 ]. 

A 8-month-old boy with hemophilia B was given plasma-derived factor IX concentrate and after 1 month developed recurrent anaphylactic reactions following infusions of factor IX, with shortness of breath, wheeze, and widespread urticaria [70 ]. High-dose factor IX immune tolerance therapy was successful in eradicating the inhibitor for 40 months. Two more attempts to achieve immune tolerance with high-dose factor IX were complicated by recurrent anaphylactic reactions. 

Drug formulations A multicenter study that compared high-purity factor IX concentrate (AlphaNine) and recombinant factor IX (BeneFIX) in patients with severe haemophilia B failed to show any adverse events (allergic type, inhibitor formation and thrombosis) in 25 patients [132. ... 

Serban M, Skotnicki AB, Colovic M, Jinca C, Klukowska A, Laguna P, et al. Clinical efficacy safety and pharmacokinetic properties of the plasma-derived factor IX concentrate Haemonine in previously treated patients with severe haemophilia B. Haemophilia 2012 18(2) 175-81. 

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