Biology and normal function of factor VIII and factor IX
- W Keith Hoots, MD
W Keith Hoots, MD
- Director, Division of Blood Diseases and Resources
- National Heart, Lung and Blood Institute
- National Institutes of Health, Bethesda, Maryland
- Amy D Shapiro, MD
Amy D Shapiro, MD
- Medical Director
- Indiana Hemophilia and Thrombosis Center
Hemostasis is the process of blood clot formation at the site of vessel injury. This process begins with the formation of the platelet plug, followed by activation of the clotting cascade and propagation of the clot. The central feature of the clotting cascade is its sequential activation of a series of proenzymes or inactive precursor proteins (zymogens) to active enzymes, resulting in significant stepwise response amplification, (eg, the generation of a small number of factor VIIa molecules will activate many molecules of factor X, which in turn generates even larger numbers of thrombin molecules). The local generation of fibrin meshes and reinforces the platelet plug (figure 1).
One of the major multicomponent complexes in the coagulation cascade is the intrinsic X-ase (ten-ase). This complex consists of activated factor IX (factor IXa) as the protease, activated factor VIII (factor VIIIa), calcium, and phospholipids as the cofactors, and factor X as the substrate. Factor IXa can be generated by either factor XIa, activation of the intrinsic pathway, or by the tissue factor/factor VIIa complex. (See "Overview of hemostasis", section on 'Multicomponent complexes'.)
Although the generation or exposure of tissue factor at the wound site is the primary physiologic event in initiating clotting via the extrinsic pathway, the intrinsic pathway X-ase is important because of the limited amount of tissue factor generated in vivo and the presence of the tissue factor pathway inhibitor which, when complexed with factor Xa, inhibits the tissue factor/factor VIIa complex. Thus, sustained generation of thrombin depends upon the activation of factor IX and factor VIII. This process is amplified because factor VIII is activated by both factor Xa and thrombin [1,2] and factor IX is activated by factor XIa via thrombin, as well as by factor VIIa; as a result, a progressive increase in factor VIII and factor IX activation occurs as factor Xa and thrombin are formed.
The biology of factor VIII and factor IX is reviewed here. Deficiencies in either of these coagulation factors lead to hemophilia (hemophilia A and hemophilia B, respectively), which is discussed separately. (See "Clinical manifestations and diagnosis of hemophilia".)
The factor VIII gene is located on the X chromosome. It is one of the largest known genes, divided into 26 exons that span 186,000 base pairs [3,4]. Factor VIII is synthesized as a single chain polypeptide of 2351 amino acids. A 19-amino acid signal peptide is cleaved by a protease shortly after synthesis so that circulating plasma factor VIII is a heterodimer.
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- FACTOR VIII
- - C2 domain
- - A2 domain
- - A1/A3-C1-C2 dimer
- - B domain
- Site of production
- Binding to von Willebrand factor
- Formation of factor VIIIa
- Intrinsic pathway X-ase
- Inactivation of factor VIIIa
- Elevated levels of factor VIII
- FACTOR IX
- Structure and function
- Inactivation of factor IXa
- Gain of function mutation