Factor VIII

• OMIM: 306700
• UniProt: P00451
• MGI: 88383

Coagulation factor VIII ( F8), antihemophilic globulin and A, is a glycoprotein and a clotting factor in vertebrates. A deficiency of clotting factor in humans leads to haemophilia A ( so-called hemophilia ). Is always cause a mutation in the F8 gene encoding Factor VIII. An intravenous supply of this blood coagulation factor is therefore the only treatment for hemophiliacs. By the end of the 1980s, factor VIII was obtained solely from donated human blood plasma, now also several recombinant preparations are available.

Factor VIII was in the 1980s the focus of one of the biggest drug scandals in Germany and throughout the world, the so-called " blood ( he ) scandal ," in which - consciously for the most part - were sold and administered contaminated factor VIII preparations, although managers in pharmaceutical industry, medicine and politics was early known that these preparations would cause HIV and hepatitis infections.

Biosynthesis

The site of synthesis of factor VIII has not been fully clarified. As a site of synthesis in addition to the liver and the endothelium and platelets discussed. The reduction takes place in the liver and kidney.

The F8 gene spans 187 000 base pairs in 26 exons. The transcribed mRNA is 9029 bases long, and is translated into a protein with 2351 amino acids, can be removed by post-translational modification of the further 19 amino acids.

The factor VIII molecule of 31 amino acid side chains with modified complex sugar molecules (25 x N- glycosylation, O-glycosylation x 6 ), the amino acid chain, is finally cut by specific proteases in two places. The final molecule consists of two chains, a 200 kDa heavy chain and a 80 kDa light chain.

Biological Function

Factor VIII, together with calcium and phospholipids ( resulting in injury ) are cofactors for factor IXa, which is necessary to activate factor X. This reaction step, is essential to the blood clotting factor Xa for activated in a complex with factor Va converts prothrombin into thrombin, and this is fibrinogen into fibrin.

Pharmacology

The substitution of factor VIII ( intravenous administration ) is the treatment of choice for hemophilia A patients. Until 1992, factor VIII was made ​​exclusively from human blood plasma. Meanwhile, among the plasma-derived and genetically engineered factor concentrates such as octocog alfa available.

Production of plasma

Factor VIII is derived from human plasma by cold precipitation ( cryoprecipitation ) and then purified by chromatography. An important goal in production is the inactivation of potential pathogens (eg viruses). In addition to the selection of the dispenser and the test of the plasma processed include inactivating the production steps such as solvent, detergent treatment (S / D process, inactivation of enveloped viruses ), heat and / or nanofiltration to the present standard of safety.

Octocog alfa

Octocog alfa ( INN) is recombinantly produced human factor VIII, which has areas of application as a drug identical to the plasma-derived factor VIII. Chemically, it differs only slightly from this. The following remarks apply to octocog alfa.

Octocog alfa is not extracted from human blood plasma, but is produced by recombinant DNA technology: it is made of a cell in which a gene has been introduced, which makes it able for the expression of human coagulation factor VIII ( see also Pharmaceutical Biotechnology ).

Posology and method of administration

The dosage and frequency of administration depends on whether factor VIII is used to treat bleeding, for the prevention of bleeding or as part of a surgical procedure. The dosage is adjusted also depends on the severity of the bleeding and the type of surgical procedure.

Contraindications

Contraindicated are all analgesics with platelet aggregation- inhibiting activity, particularly aspirin. Indicated for example, dextropropoxyphene, Tilidin naloxone, Pentetocin, buprenorphine, paracetamol, diclofenac.

Adverse effects

Patients with haemophilia A may develop antibodies (inhibitors ) to factor VIII, causing it to be disabled completely or partially. This leads to a so-called " haemophilia ", a blood flow, despite the use factor of conventional dosages. Patients with such inhibitors are divided into "low responders " and "high responders." Inhibitors may regress spontaneously in low responders rather than in high responders. Treatment of acute hemorrhage is symptomatic. The causal treatment is the elimination or reduction of the inhibitors by generating an immune tolerance ( immune tolerance induction, ITI) and should always be sought. Both in the symptomatic treatment of acute bleeding as well as the inhibitor elimination factor concentrates must be administered in high doses.

On the market there are the genetic blood clotting factor VIII in different variants. These are divided into 1st, 2nd and 3rd generation. Octocog alfa is the 2nd generation. All preparations were long regarded as equivalent to the RODIN study in 2013 found that the second generation often inhibitory to the formation of antibody preparations leads, as preparations of the third generation. The EMA decided but still no restrictions on the use of octocog recommended alfa, because the differences could also be a chance finding.

In an allergic reaction after the start of infusion, the infusion should be stopped and changed to another drug. In an anaphylactic reaction, the usual emergency treatment measures apply.

" Blood ( he ) scandal " in the 1980s

In the 1980s it came from contaminated donor blood in hemophiliacs worldwide to HIV and Hepatitis Infections - initially due to ignorance, later mainly due to negligence, conscious Ignoring warnings and profiteering. In Germany at that time about 43% of hemophiliacs were infected with HIV. This was in some countries as " blood ( he ) scandal " since pharmaceutical industry and politics concealed them known contamination and the associated risks to the public, and so a - next to the thalidomide case - caused the greatest medical scandals, consequently, at least 10,000 then infected hemophiliacs died worldwide with HIV alone until the mid- 2000s. Although there starting in March 1983 gave expert warnings from contaminated specimens and the people responsible pointed to the competent subsidiary of Bayer AG in January 1983 in internal pleadings before transmission through contaminated factor VIII blood products, infectious preparations were at least until the summer of 1995 distributed and administered accordingly.

In Germany in 1993, about ten years later, a specific investigation committee "HIV infections through blood and blood products " set up by the German Bundestag. In October 1993, the then President of the Federal Health Office Dieter Großklaus was released and dissolved the office itself the end of June 1994. At this time, over 400 of the infected period in question hemophiliacs had already died from HIV infection. Other persons acting in the scandal from the pharmaceutical industry, medicine and politics have not been prosecuted in Germany. 2013 this scandal has been processed by the ZDF in the fictional TV movie blood money and accompanying documentation.