Factor Xa: Thrombokinase from Paul Morawitz to J Haskell Milstone


In 1904 Paul Morawitz postulated that an enzyme, which he named thrombokinase, would be the primary activator of prothrombin. Fifty years passed before J Haskell Milstone isolated, purified and functionally characterized the enzyme we now call Factor Xa. This essay summarizes Milstone’s work on thrombokinase, and finds context for why his efforts succeeded while others struggled.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    p. 301–2 in [4]

  2. 2.

    p.413 in [13]

  3. 3.

    p.438 in [13]

  4. 4.

    p.421 in [13]


  1. 1.

    Morawitz P (1904) Beitrage zur Kenntnis der Blutgerinnung. Deutsches Archiv fur Klinische Medizin 79:432–442

    Google Scholar 

  2. 2.

    Morawitz P (1958) The chemistry of blood coagulation (trans: Robert C. Hartmann M, Paul F. Geunther M, PhD). American Lecture Series (1) Charles C Thomas, Springfield Illinois

  3. 3.

    Milstone JH (1947) Prothrombokinase and the three stages of blood coagulation. Science 106(2762):546–547. https://doi.org/10.1126/science.106.2762.546-a

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Milstone JH (1948) Three-stage analysis of blood coagulation. J Gen Physiol 31(4):301–324. https://doi.org/10.1085/jgp.31.4.301

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Milstone JH (1951) Fractionation of plasma globulin for prothrombin, thrombokinase, and accessory thromboplastin. J Gen Physiol 35(1):67–87. https://doi.org/10.1085/jgp.35.1.67

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Milstone JH (1952) Bovine serum as a complement for the combined effects of thrombokinase and cephalin. Yale J Biol Med 25(3):173–175

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Milstone JH (1949) The chain reaction of the blood clotting mechanism in relation to the theory of hemostasis and thrombosis. Blood 4(12):1290–1297

    CAS  Article  Google Scholar 

  8. 8.

    Milstone JH, Oulianoff N, Milstone VK (1963) Outstanding characteristics of Thrombokinase isolated from bovine plasma. J Gen Physiol 47:315–327. https://doi.org/10.1085/jgp.47.2.315

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Milstone JH (1960) Chromatography of blood thrombokinase on 'DEAE'-cellulose. Nature 187:1127–1128. https://doi.org/10.1038/1871127a0

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Milstone JH (1964) Thrombokinase as prime activator of prothrombin: historical perspectives and present status. Fed Proc 23:742–748

    CAS  PubMed  Google Scholar 

  11. 11.

    Aronson DL, Menache D (1966) Chromatographic analysis of the activation of human prothrombin with human thrombokinase. Biochemistry 5(8):2635–2640. https://doi.org/10.1021/bi00872a022

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Stenn KS, Blout ER (1972) Mechanism of bovine prothrombin activation by an insoluble preparation of bovine factor X a (thrombokinase). Biochemistry 11(24):4502–4515. https://doi.org/10.1021/bi00774a012

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Milstone JH (1952) On the evolution of blood clotting theory. Medicine (Baltimore) 31(4):411–447. https://doi.org/10.1097/00005792-195212000-00004

    CAS  Article  Google Scholar 

  14. 14.

    Milstone H (1941) A factor in Normal human blood which participates in streptococcal fibrinolysis. J Immunol 42(2):109–116

    CAS  Google Scholar 

  15. 15.

    Milstone H (1942) Purification of thrombin. J Gen Physiol 25(5):679–687

    CAS  Article  Google Scholar 

  16. 16.

    Wright IS (1958) Nomenclature of blood clotting factors; acceptance by the international committee on nomenclature of four factors, their characteristics and international number. Can Med Assoc J 80(8):659–661

    CAS  PubMed  Google Scholar 

  17. 17.

    Jaques LB (1960) Nomenclature for blood clotting factors. Can Med Assoc J 82:1327–1330

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Esnouf MP, Williams WJ (1962) The isolation and purification of a bovine-plasma protein which is a substrate for the coagulant fraction of Russell's-viper venom. Biochem J 84:62–71. https://doi.org/10.1042/bj0840062

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Macfarlane RG (1964) An Enzyme Cascade in the Blood Clotting Mechanism, and Its Function as a Biochemical Amplifier. Nature 202:498–499. https://doi.org/10.1038/202498a0

    CAS  Article  Google Scholar 

  20. 20.

    Davie EW, Ratnoff OD (1964) Waterfall Sequence for Intrinsic Blood Clotting. Science 145(3638):1310–1312. https://doi.org/10.1126/science.145.3638.1310

    CAS  Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Leonard M. Milstone.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Milstone, L.M. Factor Xa: Thrombokinase from Paul Morawitz to J Haskell Milstone. J Thromb Thrombolysis (2021). https://doi.org/10.1007/s11239-021-02387-6

Download citation


  • Thrombokinase
  • Factor X
  • Coagulation
  • Enzyme
  • Zymogen
  • Protein purification