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Blood Coagulation Factor
Written by: Hanna Fleisher

Dear friends, we continue investigating the area of scientific history of patents and pharmaceuticals. Let us remind you that when conducting patent research (e.g., various searches, expert opinions, patent strategies, etc.), we study the development of certain pharmaceutical areas and active substances. It is not for everyone :). But those who are familiar with the matter and curious about development of science in the pharmaceutical direction may be interested. Therefore, we invite you to read our new article.

Today’s article addresses Blood Coagulation Factor.

Coagulation factors are a group of related proteins that are necessary for the formation of platelet-fibrin clots, more simply – blood clots. Coagulation factors include 13 representatives: I fibrinogen, II prothrombin, III tissue factor, IV calcium ions, V proaccelerin, VII proconvertin, VIII antihemophilic globulin, IX Christmas factor, X Stewart-Prower factor, XI Rosenthal factor, XII Hageman factor and XIII a factor that stabilizes fibrin.

Coagulation factor VIII was first discovered in 1937, but it was not until 1979 that its purification by Edward Tuddenham, Francis Rothblatt and co-workers led to the molecular identification of the protein.

Coagulation factor VIII is a combination of a protein and a complex carbohydrate component that participates in phase 1 of blood coagulation and ensures the interaction of coagulation factors IX and X. The molecule of coagulation factor VIII is a heterodimer consisting of a light chain (domains A3, C1 and C2), a heavy chain (domains A1 and A2) and domain B. At the same time, the molecule contains 2332 amino acid residues (at maximum length).

In humans, factor VIII is encoded by the F8 gene. In the blood, coagulation factor VIII mainly circulates in the form of a complex consisting of three subunits, which are designated VIII-k (coagulant subunit), VIII-AG (the main antigenic marker) and VIII-fB (Willebrand factor associated with VIII-AG). After activation by thrombin (factor IIa), it is separated from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor for factor IXa in the activation of factor X, which in turn, together with its cofactor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin, which polymerizes and binds (using factor XIII) to form a blood clot.

Mutations in the F8 gene cause hemophilia A. More specifically, the mutations lead to the production of an abnormal version of coagulation factor VIII or reduce the amount of this protein. The altered or missing protein cannot effectively participate in the blood clotting process. As a result, blood clots cannot form properly in response to injury. These clotting problems lead to excessive bleeding that is difficult to control. Moreover, hemorrhages occur not only during trauma or surgical intervention, but also spontaneously – in the joints and muscles.

Actually, in the 1950s and 1960s, the treatment of hemophilia included transfusion of whole blood or fresh frozen plasma. The concentration of coagulation factor VIII in these products was not sufficient to overcome the problem of severe bleeding. One of the methods of increasing the concentration of coagulation factors was the cryoprecipitation method, i.e. slow thawing of freshly frozen plasma at a temperature of 1-6 oC. Then, for the first time, it became possible to administer sufficient amounts of coagulation factor VIII in relatively small volumes.

In the late 1960s, a method was developed to separate coagulation factor VIII from plasma to obtain a lyophilized concentrate. Therefore, truly successful and effective treatment of hemophilia did not begin until the 1970s, when the increased availability of lyophilized concentrates and the widespread use of the replacement therapy at home made it possible to control bleeding in the early stages.

The next stage of development was caused by sad events in the field of health care – the spread of HIV and hepatitis C among patients with hemophilia. It was not immediately possible to identify the cause, but in the end the culprit turned out to be medical products derived from human blood. Moreover, the problem became widespread, as the products of the giants, such as Alpha Therapeutic Corporation, Institut Mérieux (now part of Sanofi), Bayer Corporation and Baxter International, turned out to be carriers of the viruses. Initially, efforts were focused on virus inactivation by methods of drying, solvent treatment, and pasteurization. Subsequently, the principle of inactivation was supplemented with a more effective approach to the selection of plasma donors, in particular, this was facilitated by the discovery of antibodies to the hepatitis C virus and HIV.

In 1984, the coagulation factor VIII gene was cloned, which laid the foundation for the development of the drugs based on recombinant coagulation factor VIII. The first drug based on recombinant coagulation factor VIII protein was approved by the FDA in 1992. First-generation drugs were obtained by inserting the complete cDNA sequence of coagulation factor VIII into an expression vector, as a result of which the producer cells synthesized full-length recombinant human coagulation factor VIII protein. Second-generation drugs are recombinant coagulation factor VIII protein with the B-domain deleted.

Current researches on the improvement of coagulation factor VIII drugs are focused on reducing the frequency of dosing and decreasing the immunogenic potential of the drug. Today, these goals are proposed to be achieved by the development of recombinant drugs obtained using a human cell line in order for coagulation factor VIII to have maximum similarity with human proteins; by modifying the coagulation factor VIII molecule, for example, by modifying the amino acid sequence; obtaining single-stranded coagulation factor VIII; obtaining constructs, for example, fusion proteins (with the Fc-fragment of immunoglobulin G, albumin or von Willenbrand factor); and pegylation of coagulation factor VIII.

Purified plasma coagulation factor VIII is still the standard in the treatment of hemophilia A today. However, along with this, its recombinant form is gaining wider use. It is clearly observed that, as in the case of immunoglobulins, the medical industry seeks to replace blood plasma with other sources independent of humans.

Thanks to everyone who read and was interested.

Best regards,

Team of Intectica group.

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