Factor VIII

Factor VIII Coagulation proteins hemophilia A treatment 300 3 X 10- ... 

Immunoaffinity chromatography utilizes the high specificity of antigen—antibody interactions to achieve a separation. The procedure typically involves the binding, to a soHd phase, of a mouse monoclonal antibody which reacts either directly with the protein to be purified or with a closely associated protein which itself binds the product protein. The former approach has been appHed in the preparation of Factor VIII (43) and Factor IX (61) concentrates. The latter method has been used in the preparation of Factor VIII (42) by immobilization of a monoclonal antibody to von WiHebrand factor [109319-16-6] (62), a protein to which Factor VIII binds noncovalenfly. Further purification is necessary downstream of the immunoaffinity step to remove... 

Factor VIII, immunoglobulin, and albumin are all held as protein precipitates, the first as cryoprecipitate and the others as the Cohn fractions FI + II + III (or FII + III) and FIV + V (or FV), respectively (Table 7, Fig. 2). Similarly, Fractions FIVj + FIV can provide an intermediate product for the preparation of antithrombin III and a-1-proteinase inhibitor. This abiUty to reduce plasma to a number of compact, stable, intermediate products, together with the bacteriacidal properties of cold-ethanol, are the principal reasons these methods are stiU used industrially. 

Another by-product of Factor VIII processing having clinical value is von Wikebrand factor. It has been recovered from side fractions using ion-exchange and affinity chromatography (196). 

Estimates for a number of economic aspects of plasma fractionation can be made (200—206). The world capacity for plasma fractionation exceeded 20,000 t of plasma in 1990 and has increased by about 75% since 1980, with strong growth in the not-for-profit sector (Fig. 4). The quantity of plasma processed in 1993 was about 17,000 t/yr the commercial sector accounts for about 70% of this, with over 8000 t/yr in the form of source plasma from paid donors (Fig. 5). Plant capacities and throughput are usually quoted in terms of principal products, such as albumin and Factor VIII. These figures may not encompass manufacture of other products. 

Fig. 6. Share of U.S. market occupied by human albumin/plasma protein fraction, (—) Factor VIII concentrate, (-) intravenous immunoglobulin...

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

Determination of the potency of Factor VIII is also difficult. This is normally measured by the abiUty of the sample to correct the clotting time of plasma deficient in Factor VIII. A number of methods and practices have evolved for this purpose (231), but these give very different results, particularly when activation of products may also occur (232). International standards have been used, but further standardization of the analytical method and harmonization of working standards is underway (233,234) under the auspices of the ISTH and the EC. 

Initial the shorter initial half-Hves for Factors VIII and IX are probably because of distribution into extravascular compartments. 

Deficiency of the VIIFC portion of the Factor VIII complex results in classic hemophilia or hemophilia A and is inherited as a sex-linked recessive disorder. Based on the degree of deficiency of the VIIFC molecule three different forms of hemophilia A are recognized. Less than 1% VIIFC activity equals severe hemophilia A. Two to 10% of normal VIIFC activity equals moderately severe hemophilia A. Ten to 25% of normal VIIFC activity equals minimal symptomatic disease. Deficiency of the VIIFvWFAg portion of the Factor VIII complex results in von WiUebrand disease. There are at present five principal types of von WiUebrand disease and numerous subtypes or variants. For the most part, von WiUebrand disease is inherited as an autosomal dominant, and a few subtypes may be inherited as an autosomal recessive trait. 

Coagulation Factor VIII-SD VIII C Vactor T7/I SD New York Blood Center... 

Coagulation Factor VIII-SD VIIFC SD American Red Cross... 

Antihemophilic factor [9001-28-9] (AHF) is a protein found in normal plasma that is necessary for clot formation. It is needed for transformation of prothrombin to thrombin. Administration of AHF by injection or infusion can temporarily correct the coagulation defect present in patients with hemophilia. Antihemophilic factor VIII (Alpha Therapeutic) has been approved by the FDA as replacement therapy in patients with hemophilia B to prevent bleeding episodes, and also during surgery to correct defective hemostasis (178). 

In past years, treatment for patients with hemophilia A has consisted of administration of cryoprecipitates (enriched in factor VIII) prepared from individual donors or lyophilized factor VIII concentrates prepared from plasma pools of up to 5000 donors. It is now possible to prepare factor Vlll by recombinant DNA technology. Such preparations are free of contaminating viruses (eg, hepatitis A, B, G, or HlV-1) found in human plasma but are at present expensive their use may increase if cost of production decreases. 

Inherited deficiencies of the clotting system that result in bleeding are found in humans. The most common is deficiency of factor VIII, causing hemophilia A, an X chromosome-hnked disease that has played a major role in the history of the royal families of Europe. Hemophilia B is due to a deficiency of factor IX its clinical Feamres are almost identical to those of hemophilia A, but the conditions can be separated on the basis of specific assays that distinguish between the two factors. 

Genetic disorders of coagulation factors occur, and the two most common involve factors VIII (hemophilia A) and IX (hemophilia B). 

---