Download PDF
Thromb Haemost 1985; 54(03): 650-653
DOI: 10.1055/s-0038-1660090
Original Article
Schattauer GmbH Stuttgart

The Functional Defect of Factor VIII Leiden, a Genetic Variant of Coagulation Factor VIII

K Mertens
The Haemostasis and Thrombosis Research Unit, Leiden University Hospital, Leiden, The Netherlands
,
A van Wijngaarden
The Haemostasis and Thrombosis Research Unit, Leiden University Hospital, Leiden, The Netherlands
,
R M Bertina
The Haemostasis and Thrombosis Research Unit, Leiden University Hospital, Leiden, The Netherlands
,
J J Veltkamp
The Haemostasis and Thrombosis Research Unit, Leiden University Hospital, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 17 June 1985

Accepted 30 July 1985

Publication Date:
26 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Factor VIII Leiden is a genetic variant of coagulation factor VIII which has been detected in the plasma of a patient with mild haemophilia A. In this patient’s plasma factor VIII procoagulant antigen was in 5-fold excess over factor VIII procoagulant activity, indicating the presence of an abnormal factor VIII molecule. The variant factor VIII was isolated from the patient’s plasma, and its functional properties were studied in a factor X-activating system consisting of purified components. The isolated factor VIII Leiden was normally activated by factor Xa and by thrombin, but the activity of the factor Villa was about 3% of normal. The defect of factor Villa Leiden was studied by comparison with normal factor Villa in kinetic experiments of factor Xa formation. The results support the hypothesis that factor Villa Leiden has a reduced affinity for phospholipid-bound factor IXa in the intrinsic factor X-activating complex.

Keywords

Factor VIII - Genetic variant - Haemophilia A+ - Factor X activation
 

  • References

  • 1 Zimmerman TS, Meyer D. Structure and function of factor VUI/von Willebrand factor. In: Haemostasis and Thrombosis Bloom AL, Thomas DP. (eds.) 111-123 Churchill Livingstone; Edinburgh: 1981
  • 2 Hoyer LW. The factor VIII complex: structure and function. Blood 1981; 58: 1-13
    PubMedGoogle Scholar
  • 3 Hoyer LW, Beckenridge RT. Immunologic studies of antihemophilic factor (AHF, factor VIII): cross-reacting material in a genetic variant of hemophilia A. Blood 1968; 32: 962-971
    PubMedGoogle Scholar
  • 4 Denson K WE, Biggs R, Haddon ME, Borrett R, Cobb K. Two types of haemophilia (A+ and A-). A study of forty-eight cases. Br J Haematol 1969; 17: 163-171
    PubMedGoogle Scholar
  • 5 Feinstein D, Chong M NY, Kasper CK, Rapaport SI. Hemophilia A: polymorphism detectable by a factor VIII antibody. Science 1969; 163: 1071-1072
    CrossrefPubMedGoogle Scholar
  • 6 Reisner HM, Price WA, Blatt PM, Barrow ES, Graham JB. Factor VIII coagulant antigen in hemophilic plasma: a comparison of five alloantibodies. Blood 1980; 56: 615-619
    PubMedGoogle Scholar
  • 7 Girma JP, Lavergne JM, Meyer D, Larrieu MJ. Immunoradiometric assay of factor VIII: Coagulant antigen using four human antibodies. Study of 27 cases of haemophilia A. Br J Haematol 1981; 47: 269-282
    PubMedGoogle Scholar
  • 8 Muller HP, van Tilburg NH, Bertina RM, Veltkamp JJ. Heterogeneity of haemophilia A. A study with three different antisera. Br J Haematol 1982; 52: 485-494
    PubMedGoogle Scholar
  • 9 Jackson CM, Nemerson Y. Blood coagulation. Annu Rev Biochem 1980; 49: 765-811
    CrossrefPubMedGoogle Scholar
  • 10 van Dieijen G, Tans G, Rosing J, Hemker HC. The role of phospholipid and factor Villa in the activation of bovine factor X. J Biol Chem 1981; 256: 3433-3442
    PubMedGoogle Scholar
  • 11 Link RP, Castellino FJ. Kinetic comparison of bovine blood coagulation factors IXaa and IXap toward bovine factor X. Biochemistry 1983; 22: 4033-4041
    CrossrefPubMedGoogle Scholar
  • 12 Mertens K, Bertina RM. The contribution of Ca2+ and phospholipids to the activation of human blood-coagulation factor X by activated factor IX. Biochem J 1984; 223: 607-615
    CrossrefPubMedGoogle Scholar
  • 13 Vehar GA, Davie EW. Preparation and properties of bovine factor VIII (anti-hemophilic factor). Biochemistry 1980; 19: 401-410
    CrossrefPubMedGoogle Scholar
  • 14 Mertens K, Bertina RM. Activation of human coagulation factor VIII by activated factor X, the common product of the intrinsic and the extrinsic pathway of blood coagulation. Thromb Haemostas 1982; 47: 96-100
    PubMedGoogle Scholar
  • 15 Mertens K, van Wijngaarden A, Bertina RM. The role of factor VIII in the activation of human blood coagulation factor X by activated factor IX. Thromb Haemostas 1985; 54: 654-660
    PubMedGoogle Scholar
  • 16 Griffith MJ, Reisner HM, Lundblad RL, Roberts HR. Measurement of human factor IXa activity in an isolated factor X activation system. Thromb Res 1982; 27: 289-301
    CrossrefPubMedGoogle Scholar
  • 17 Mertens K, Cupers R, van Wijngaarden A, Bertina RM. Binding of human blood-coagulation factors IXa and X to phospholipid membranes. Biochem J 1984; 223: 599-605
    CrossrefPubMedGoogle Scholar
  • 18 Veltkamp JJ, Drion EF, Loeliger EA. Detection of the carrier state in hereditary coagulation disorders. I. Thrombos Diathes Haemorrh 1968; 19: 279-303
    PubMedGoogle Scholar
  • 19 Muller HP, van Tilburg NH, Bertina RM, Terwiel JPh, Veltkamp JJ. Immunoradiometric assay of procoagulant factor VIII antigen (VIIICAg). Clin Chim Acta 1980; 107: 11-19
    CrossrefPubMedGoogle Scholar
  • 20 Mertens K, Cupers R, van der Linden IK, Bertina RM. The functional defect of factor IX Eindhoven, a genetic variant of factor IX. Thromb Haemostas 1983; 50: 249 (Abstr.)
    PubMedGoogle Scholar