450 million years of hemostasis

J Thromb Haemost. 2003 Jul;1(7):1487-94. doi: 10.1046/j.1538-7836.2003.00334.x.


In mammalian blood coagulation, five proteases (factor VII [FVII]; factor IX [FIX]; factor X [FX]; protein C [PC] and prothrombin [PT]) act with five cofactors (tissue factor [TF]; factor V [FV]; factor VIII [FVIII]; thrombomodulin and protein S) to control the generation of fibrin. Biochemical evidence, molecular cloning data and comparative sequence analysis support the existence of all components of this network in all jawed vertebrates, and strongly suggest that it evolved before the divergence of teleosts over 430 million years ago. Phylogenetic analysis of the amino acid sequences of the Gla-EGF1-EGF2-SP domain serine proteases (FVII, FIX, FX, PC) and the A domain-containing cofactors (FV and FVIII) strongly supports the evolution of the blood coagulation network through two rounds of gene duplication, and supports the hypothesis that vertebrate evolution benefited from two global genome duplications. The jawless vertebrates (hagfish and lamprey) that diverged over 450 million years ago have a blood coagulation network involving TF, PT and fibrinogen. Preliminary evidence indicates that they may have a smaller complement of Gla-EGF1-EGF2-SP domain proteins, suggesting the existence of a 'primitive' coagulation system in jawless vertebrates.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Evolution
  • Factor IX / chemistry
  • Factor VII / chemistry
  • Factor X / chemistry
  • Fibrinogen / chemistry
  • Hemostasis / physiology*
  • Humans
  • Models, Biological
  • Models, Genetic
  • Phylogeny
  • Protein C / chemistry
  • Protein Structure, Tertiary
  • Prothrombin / chemistry


  • Protein C
  • Factor VII
  • Prothrombin
  • Factor IX
  • Factor X
  • Fibrinogen