The Abnormal Factor IX of Hemophilia B⁺ Variants

Summary

A rather large proportion of the hemophilia B patients can be characterized as hemophilia B⁺ because of the presence in their plasma of a protein which is immunologically identical with human factor IX. In a group of 33 hemophilia B patients we found 14 cases of hemophilia B⁺ belonging to 11 independent pedigrees. The variant factor IX molecules of these families have been compared with respect to the following properties: 1) factor IX activity and its dependence on phospholipid concentration; 2) factor IX antigen; 3) prolongation of prothrombin time with an ox brain thromboplastin; 4) electrophoretic mobility; 5) Ca²⁺ binding capacity; 6) affinity for binding to heparin and 7) susceptibility of the factor IX antigen to contact-induced activation. In the study of these parameters the use of a precipitating antibody against highly purified human factor IX showed to be of great value. According to our criteria at least 7 different factor IX variants were present in the 11 families with hemophilia B⁺ studied. Because of this rather high heterogeneity a suitable nomenclature for subclassification of hemophilia B⁺ variants is proposed.

• References

• 1 Andersson L-O, Borg H, Miller-Andersson M. 1975; Purification and characterization of human factor IX. Thrombosis Research 7: 451
• 2 Bertina RM, Linden IK. Van Der. 1977; Inhibitor-neutralisation assay and electroimmunoassay of human factor IX (Christmas factor). Clinica chimica acta 77: 275
• 3 Briët E. 1977. Three problems of hemophilia B. A study of abnormal factor IX molecules with an inhibitor neutralization assay. M. D. Thesis; Leiden:
• 4 Davie EW, Fujikawa K, Lindquist P, Di Scipio R, Kurachi K, Heimark R. 1977; The role of factor IX (Christmas factor) in blood coagulation. Thrombosis and Haemostasis 38: 115
• 5 Denson KW E, Biggs R, Mannucci PM. 1968; An investigation of three patients with Christmas disease due to an abnormal type of factor IX. Journal of Clinical Pathology 21: 160
• 6 Di Scipio RG, Hermodson MA, Yates SG, Davie EW. 1977; A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry 16: 698
• 7 Elödi S, Puskás E. 1972; Variants of haemophilia B. Thrombosis et Diathesis Haemorrhagica 28: 489
• 8 Girolami A, Sticchi A, Burul A, Dal Bozanon R. 1977; An immunological investigation of hemophilia B with a tentative classification of the disease into five variants. Vox Sanguinis 32: 230
• 9 Graham JB, Barrett II DA, Blömback B, Cann HM, Hardisty RM, Larrieu MJ, Renwick JH. 1973; Reports from the International Committee of Haemostasis and Thrombosis. I. A genetic nomenclature for human blood coagulation. Thrombosis et Diathesis Haemorrhagica 30: 2
• 10 HOUGIE C, TWOMEY JJ. 1967; Haemophilia Bm: A new type of factor-IX deficiency. Lancet I: 689
• 11 Kasper CK, ØSterud B, Rapaport SI. 1977; Hemophilia B: genetic variants and carrier detection. Thrombosis and Haemostasis 38: 116
• 12 Lavergne JM, Josso F. 1975. Metabolism of PIVKA II in man. In: Hemker HC, Veltkamp JJ. (ed.) Prothrombin and Related Coagulation Factors, Boerhaave series no 10. Leiden University Press; Leiden: p 183
• 13 Lindhout MJ, Kop-Klaassen BH M. 1975. Proteins induced by vitamin K antagonists (PIVKAs). In: Hemker HC, Veltkamp JJ. (ed.) Prothrombin and Related Coagulation Factors, Boerhaave series no 10. Leiden University Press; Leiden: p 274
• 14 Lowry O, Roseborough N, Farr A, Randall R. 1951; Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry 193: 265
• 15 Matsuoka M, Masakazu I, Takahashi K, Sakuragawa N. 1976; An immunological method for detection of the carrier of hemophilia B. Thrombosis and Haemostasis 36: 441
• 16 Ménaché D. 1977; Clinical use of factor IX concentrates. Thrombosis and Haemostasis 38: 117
• 17 Meyer D, Larrieu MJ. 1971; Factor VIII and IX variants. Relationship between haemophilia BM and haemophilia B⁺ European Journal of Clinical Investigation 1: 425
• 18 Nossel HL. 1964. The Contact Phase of Blood Coagulation. Blackwell Scientific Publications; Oxford:
• 19 Ørstavik KH, Østerud B, Prydz H, Berg K. 1975; Electroimmunoassay of factor IX in hemophilia B. Thrombosis Research 7: 373
• 20 Østerud B, Flengsrud R. 1975; Purification and some characteristics of the coagulation factor IX from human plasma. Biochemical Journal 145: 469
• 21 Østerud B, Laake K, Prydz H. 1975; The activation of human factor IX. Thrombosis et Diathesis Haemorrhagica 33: 553
• 22 Pfueller S, Somer JB, Castaldi PA. 1969; Haemophilia B due to an abnormal factor IX. Coagulation 2: 213
• 23 Roberts HR, Grizzle JE, Mclester WD, Penick GD. 1968; Genetic variants of hemophilia B: Detection by means of a specific PTC inhibitor. Journal of Clinical Investigation 47: 360
• 24 Rosenberg JS, Mckenna PW, ROSENBERG RD. 1975; Inhibition of human factor IXa by human antithrombin. Journal of Biological Chemistry 250: 8883
• 25 Suomela H. 1976; Human coagulation factor IX. Isolation and characterization European Journal of Biochemistry 71: 145
• 26 Suomela H, Blombäck M, Blombäck B. 1977; The activation of factor X evaluated by using synthetic substrates. Thrombosis Research 10: 267
• 27 Thompson AR. 1977; Factor IX antigen by radioimmunoassay. Abnormal factor IX protein in patients on warfarin therapy and with hemophilia B Journal of Clinical Investigation 59: 900
• 28 Varadi K, Hemker HC. 1976; Kinetics of the formation of the factor IX activating enzyme of the blood coagulation system. Thrombosis Research 8: 303
• 29 Veltkamp JJ, Drion EF, Loeliger EA. 1968; Detection of the carrier state in hereditary coagulation disorders. I. Thrombosis et Diathesis Haemorrhagica 19: 279
• 30 Weber K, Osborn M. 1969; The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide gel electrophoresis. Journal of Biological Chemistry 244: 4406