Factor VIII

Factor VIII (FVIII) is an essential clotting factor. The lack of normal FVIII causes Hemophilia A, an inherited bleeding disorder.

This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder.^[1]

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Genetics

The gene for Factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as in one of its introns another gene is embedded.^[2].

Physiology

FVIII is a glycoprotein procofactor synthesized and released into the bloodstream by the endothelium. In the circulating blood, it is mainly bound to von Willebrand factor (vWF, also known as Factor VIII-related antigen) to form a stable complex. Upon activation by thrombin or factor Xa, it dissociates from the complex to interact with Factor IXa the coagulation cascade. It is a cofactor to Factor IXa in the activation of Factor X, which, in turn, with its cofactor Factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using Factor XIII) into a blood clot.

No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated Protein C and Factor IXa) and quickly cleared from the blood stream.

Factor VIII is synthesized predominantly in the vascular endothelium and is not affected by liver disease. In fact, levels usually are elevated in such instances.^[3]

Therapeutic use

FVIII concentrated from donated blood plasma (Aafact), or alternatively recombinant FVIII can be given to hemophiliacs to restore hemostasis. Thus, FVIII is also known as Anti-hemophilic factor.

The transfer of a plasma byproduct into the blood stream of a patient with hemophilia often led to the transmission of diseases such as HIV and hepatitis B and C before purification methods were improved. In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy. In particular, some pharmaceutical companies such as Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available.^[4]

References

Further reading