Hemophilia recombinant factor

Natural source may carry risk of infection. Recombinant Factor VIII used to treat hemophilia A has helped reduce the incidence of HIV infection in hemophiliacs. Recombinant HbsAg is now used to immunize against hepatitis B, eliminating the risk of introducing a viral infection during vaccination. 

Clinical trials have demonstrated excellent efficacy with recombinant human factor VIII concentrates available as Recombinate and Kogenate. These recombinant factor VIII products are purified from the cell culture of plasmids, not viral DNA-transfected hamster cells and therefore do not express viral sequences. The addition of human serum albumin for stabilization, constitutes the sole possible source for human viral contamination. More recently recombinant factor IX has been genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line. It has been proved to be safe and effective in the treatment of patients with hemophilia B. 

F. Place in therapy Micromedex notes that the major use of factor IX is in the therapy of hemophilia B, but it may also be useful in patients with clotting disorders secondary to hepatic dysfunction and other conditions. Recombinant factor IX BeneFix), however, is used specifically for the prevention and control of bleeding in patients with hemophilia B. 

E Role in therapy Antihemophilic factor is indicated for the treatment of bleeding episodes or perioperative treatment in patients with hemophilia A. Prophylactic use has also been advocated for the prevention and/or reduction of bleeding episodes. The largest issue in treatment with antihemophilic factor is the choice of formulations because of the relative risk of viral transmission. Recombinant factor VIII has the lowest risk of transmission of blood-borne viruses, but its use may be limited due to cost and availability. 

VIII Hemophilia A 30-50% 100% for major bleeding or trauma 12 hours Recombinant factor VIII products Plasma-derived high purity concentrates Cryoprecipitate1 Some patients with mild deficiency will respond to DDAVP... 

Blood factor VIII (FVIII) is a glycoprotein with 2351 amino acids and 330 kDa. Its deficiency causes hemophilia A. The first products based on recombinant factor VIII to reach the market were Recombinate and Kogenate, expressed in CHO and BHK cells, respectively. Over the last decade, other rFVIII products were approved, with modifications to the molecule (e.g. deletion of the B-domain), in the formulation or in the production processes. 

Giles AR,Tinlin S, Hoogendoorn H, Fournel MA, Ng P, Pancham N. In vivo characterization of recombinant factor VIII in a canine model of hemophilia a (factor VIII deficiency). Blood 1988 72 335-9. 

Lusher JM, Arkin S, Abildgaard CF, et al. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A safety, efficacy, and development of inhibitors. N Engl J Med 1993 328(7) 453—9. 

In the past, hemophiliacs were treated with transfusions of a concentrated plasma fraction containing factor VIII. This therapy carried the risk of infection. Indeed, many hemophiliacs contracted hepatitis and AIDS. A safer preparation of factor VIII was urgently needed. With the use of biochemical purification and recombinant DNA techniques, the gene for factor VIII was isolated and expressed in cells grown in culture. Recombinant factor VIII purified from these cells has largely replaced plasma concentrates in treating hemophilia. 

Inhibitor formation has been observed in only a few patients with factor XI deficiency. Like patients with hemophilia A and B, these patients may be treated with prothrombin complex concentrates or recombinant factor Vila (2). 

Thrombophlebitis at the infusion site is a common complication of continuous infusion of various clotting factor concentrates and has been noted after infusion of factor Vila (9,10). Thrombophlebitis occurred in one of eight hemophiliacs with inhibitors who received continuous infusion of recombinant factor Vila to allow elective surgery (11). In 25 hemophilia patients with inhibitors, who received recombinant factor Vila for surgical procedures or spontaneous bleeding, there was one case of thrombophlebitis in 35 continuous infusion courses (12). In most instances, thrombophlebitis can be prevented by parallel infusion of saline or heparin. 

In two patients with hemophilia with antibodies to both human and porcine factor VIII, continuous recombinant factor Vila resulted in hematuria (21). In neither case was a cause of the hematuria found. The author suggested that mucosal bleeds, such as hematuria, are characterized by high fibrinoljdic activity locally and may require higher peak concentrations of factor VII to generate sufficient thrombin to achieve and sustain hemostasis. The need for a full thrombin burst could relate to the role of thrombin in the activation of thrombin-activatable fibrinolysis inhibitor. 

The development of antibodies against recombinant factor Vila or hjrpersensitivity reactions to normal doses of recombinant factor Vila have not so far been reported (7). No antibodies against recombinant factor Vila were observed in a group of 222 hemophilia A and 16 hemophilia B patients with inhibitors treated with high doses of factor Vila (14). However, antibodies to factor VII have been observed in a patient with factor VII deficiency who received 40 times the recommended dose of recombinant activated factor Vila (3). Another case of low-titer and transient factor VII antibody formation has been reported in a patient with factor VII deficiency (10). 

Lyophilized factor VIII has been used as substitution therapy in patients with hemophilia A. Most, but not all, recombinant factor VIII (recFVIII) is structurally and immunologically similar to plasma-derived factor VIII, and it has been well tolerated by patients in clinical trials. A major concern about recombinant factor VIII has been the occurrence inhibitors (1). However, there is evidence that there is no difference in the occurrence of inhibitors between recombinant factor VIII and plasma-derived factor VIII (2). 

In two studies of previously untreated patients with severe hemophilia, who were given two different recombinant factor VIII products, the incidence of development of an inhibitor was comparable (about 30%) (29). 

In 31 previously untreated and minimally treated children with severe hemophilia A, who received full-length recombinant factor VIII (formulated with sucrose) for home therapy and surgery, there was no difference in the incidence of inhibitor formation compared with other recombinant products or plasma-derived products (2). 

Treatment options for patients with inhibitors are high dosages of clotting factor or recombinant factor Vila for both hemophilia A and B or, in the case of hemophiha A, porcine factor VlllrC or activated prothrombin complex (37). Regular administration of intermediate or low-dose factor Vin concentrates leads to the rapid disappearance of factor VIII inhibitors in some high responders (27) this is thought to be due to the development of immune tolerance. 

If the inhibitor activity is under 10 Bethesda units/ml, patients can be treated with increased doses of factor VIII or IX concentrates (43). In addition, patients with hemophilia A with low or intermediate antibody titers can also be treated with porcine factor VIII (43). However, hemorrhagic episodes in patients with antibody activity over 10 Bethesda units/ml may result in life-threatening hemorrhage that cannot be treated by conventional therapy (26,43). Prevention or treatment of clinically significant bleeding episodes in these patients can be achieved by using so-called bypassing therapies, such as recombinant factor Vila and activated prothrombin complex (23/26,43). Recombinant factor Vila is both effective and safe in the treatment of inhibitors directed to either factor VIII or IX (44,45). 

Factor IX is used as substitution therapy in patients with hemophilia B. Although the half-lives of recombinant and plasma factor IX products are comparable, the in vivo recovery of recombinant factor IX is 28% lower than a highly purified plasma-derived product. To treat hemorrhage the dosage of recombinant factor IX needs to be 20% higher than plasma-derived products to increase the circulating factor IX activity to 1% per lU of recombinant factor IX given (1). 

A young patient with hemophilia B with inhibitors developed an urticarial rash after several attempts to induce immune tolerance with a high dose of factor IX C (5). Recombinant factor IX gave rise to urticaria in patients with hemophilia B undergoing surgery (9). 

Recombinant factor concentrates are usually first-line treatment for moderate and severe hemophilia because they have the lowest risk of infection. 

Protein purification, introduced in the 1990s, produced high-purity concentrates with increased amounts of factor VIII or factor IX relative to the product s total protein content. Recombinant factor VIII and then factor IX also became available. The first-generation recombinant factor VIII products utilize human and animal proteins in culture and add human albumin as a protein stablilizer. Second-generation recombinant factor VIII concentrates removed albumin as a protein stabilizer, and the third-generation products lack human and animal proteins in the culture media. Finally, gene therapy for the treatment of hemophilia is now in the early stages of clinical trials. 

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. 

Bray GL, Gomperts ED, Courier S, et al. A multicenter smdy of recombinant factor VIII (Recombinate) Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate study group. Blood 1994 83 2428-2435. 

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. 

G.C. White II, S. Courier, G.L. Bray M. Lee, E. Gomperts, and the Recombinate Previously Treated Patient Study Group. A multicenter study of recombinant factor VIII (Recombinate ) in previously treated patients with hemophilia A. Thromb Hemost 1997 77 660-667. 

NZ BAY-14-2222 antihemophilic Kogenate FS Helixate FS, Kogenate SF Human recombinant factor VIII expressed in baby hamster kidney cells and purified by modified chromatography and then stabilized with sucrose Hemophilia... 

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