Blood clotting factor VIII

Accelerates the actions of several blood clotting factors (VIII, IX, X, XI, and XII)... 

Figure 6. Structural relationships between ascorbate oxidase, ceruloplasmin, nitrite reductase, and blood clotting factor VIII.

Rubinstein, A., "Heat treatment of lyophilized blood clotting factor VIII concentrate" U.S. patent, 4,456,590. 1984. 

Blood factor Vlll-based products are indicated for the treatment and prophylaxis of patients with hemophilia A (see also Part II, Chapters 1-3). This is a genetic disease characterized by the total lack or presence only at low levels of blood clotting factor VIII. Lack of adequate levels of this clotting factor results in prolonged bleeding episodes, occurring spontaneously or after trauma/surgery. 

Niemann H, Halter R, Carnwath J, et al. Expression of human blood clotting factor VIII in the mammary gland of transgenic sheep. Transgenic Res., 1999 8(3) 237-347. 

Defective blood clotting factor VIII leads to uncontrolled bleeding. 

Human insulin, interferon, human growth hormone, and human blood clotting factor VIII 1024 copies... 

Early studies of C. suggested an octameric structure, then a tetrameric a2P2 structure. However, gel filtration of reduced and alkylated C in 6 M guanidine hydrochloride showed that the protein from several species is a single chain of M, 120,000 the earlier results were probably proteolysis artifacts. The amino acid sequence consists of a twice repeated (i.e. 3 copies) 340-residue unit, which is 30% homologous to the A subunit of blood clotting factor VIII. [L.Ryden in R.Lontie (ed.) Copper Proteins and Copper Enzymes, CRC Press, Boca Raton, 1984 R.M.Lawn Ce//42 (1985) 405-406]... 

Liposomes have also been used for the immobilization of some other biological compunds, which are of interest from the clinical point of view. The authors of Ref. 371 have described a preparation of liposomes containing blood clotting Factor VIII, which can be used for the treatment of hemophilia. Experiments have been done on the peroral administration of Factor VIII-containing liposomes into hemophilic dogs. Angiotensin II and heparin have been also entrapped into liposomes. 

It has also been proposed that because of sequence and possible structural homology with the blood clotting factors V and VIII [6] that ceruloplasmin may also participate in blood clotting and its regulation [5]. 

In addition to its previously mentioned role in copper transport, ceruloplasmin is an amine oxidase, a superoxide dismutase, and a ferrooxidase able to catalyze the oxidation of Fe2+ to Fe3+. Ceruloplasmin contains three consecutive homologous 350-residue sequences which may have originated from an ancestral copper oxidase gene. Like ascorbate oxidase, this blue protein contains copper of the three different types. Blood clotting factors V and VIII (Fig. 12-17), and the iron uptake protein Fet3 (Section A,l) are also closely related. 

Glycoproteins Interferons Blood clotting factors (factors VIII, IX) Glycoprotein hormones, EPO Plasminogen activators, t-PA... 

Biopharmaceuticals include recombinant cytokines (interferons, IL-2, GM-CSF), blocking antibodies (such as the anti-TNF-a drug infliximab), and vaccines, as well as products not directly related to the immune system, such as blood clotting factors and hormones (Factor VIII, erythropoietin, heparin), enzymes, and hormones (Crommelin et al., 2003). 

B. Clotting Factors The most important agents used to treat hemophilia are fresh plasma and purified human blood clotting factors, especially factor VIII and factor IX, that are either purified from blood products or produced by recombinant DNA technology. These products are extremely expensive and carry a risk of infection (due to contamination by blood-home pathogens) and immunologic reactions. 

Advances in recombinant technology alleviated the problem of protein production and its purity. Through the process of recombinant DNA technology and use of nonhuman cell lines, human proteins can be manufactured free of viral contamination. This process enables production of large quantities of proteins previously difficult to obtain from human sources. Further isolation of protein from human sources is associated with a high risk of viral contamination. One such example, plasma derived clotting factor VIII isolated from human blood, resulted in transmission of viral diseases such as hepatitis and AIDS [1,2]. 

Increasingly, plasma proteins that were once measured exclusively by their catalytic activities and expressed in terms of enzyme units are now being measured by immunoassay techniques, and expressed in terms of concentration (e.g., micrograms per liter). When the results from these very different forms of analysis are compared, there is often little correlation. In many cases, this reflects the fact that proteins can exist in multiple structural forms, differing in conformational properties, in terms of proteolytic cleavage, or in terms of specific forms of post-translational modification (e.g., phosphorylation). While these forms may retain some conserved epitopes, and thus have common immunological properties, structural differences often have a profound effect on their activities. For example, it has been found that the blood protein factor VIII, which is one of the key proteins in the blood clotting cascade, loses its catalytic activity in hemophilia while... 

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