Activation of Factor VIII and Mechanisms of Cofactor Action

Blood Rev. 2004 Mar;18(1):1-15. doi: 10.1016/s0268-960x(03)00025-0.


The factor VIII procofactor circulates as a metal ion-dependent heterodimer of a heavy chain and light chain. Activation of factor VIII results from limited proteolysis catalyzed by thrombin or factor Xa, which binds the factor VIII substrate over extended interactive surfaces. The proteases efficiently cleave factor VIII at three sites, two within the heavy and one within the light chain resulting in alteration of its covalent structure and conformation and yielding the active cofactor, factor VIIIa. The role of factor VIIIa is to markedly increase the catalytic efficiency of factor IXa in the activation of factor X. This effect is manifested in a dramatic increase in the catalytic rate constant, k(cat), by mechanisms that remain poorly understood.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism
  • Down-Regulation
  • Factor VIII / chemistry
  • Factor VIII / metabolism
  • Factor VIIIa / chemistry
  • Factor VIIIa / metabolism*
  • Factor Xa / metabolism
  • Humans
  • Kinetics
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Thrombin / metabolism
  • von Willebrand Factor / metabolism


  • Neoplasm Proteins
  • von Willebrand Factor
  • Factor VIIIa
  • Factor VIII
  • Thrombin
  • Factor Xa
  • Cysteine Endopeptidases
  • cancer procoagulant