Variants of Vitamin K Dependent Coagulation Factors

Hemostasis and Thrombosis Research Unit, University Hospital Leiden, Rijnsburgerweg 10, 2333 AA Leiden (The Netherlands) Congenital disorders of blood coagulation can be due to the complete absence or decreased concentration of one of the coagulation factors or to the production of an abnormal one. The abnormal inactive coagulation factors are usually referred to as CRM-positive or CRM-reduced variants. CRM is an abbreviation for material that shows a cross-reaction with an antibody against a specific coagulation factor. True deficiencies as well as abnormal variants of the vitamin K dependent factors have been reported [1, 2, 6, 7]. Usually, the variants are detected by means of their reduced coagulant activity; the latter becomes apparent by comparison of the results of functional and immunological assays. The variants can be characterized further by biochemical methods and by their ability to be activated by nonphysiological agents like trypsin, sta-phylocoagulase, snake venoms and a number of thromboplastins. At the moment it appears that the severity of the bleeding symptoms only correlates with the residual coagulant activity. The accompanying paper of Girolami et ah [this issue] reports on the observation of a pedigree with a genetic variant of factor VII very similar to factor VII Padua. The factor VII Padua, described by the same authors [4], is the first genetic variant of factor VII of which the nature of the underlying defect might be hypothesized: it is highly probable that the mutation has occurred in that part of the molecule that is responsible for its interaction with the tissue factor. Apart from these two (possibly related) families eight other families have been reported to have a variant of factor VII with a strongly reduced coagulant activity. At present we know 9 defective variants of factor II (Barcelona, Quick, Cardeza, San Juan, Brussels, Padua, Mouse, Madrid, Metz), 5 variants of factor X (Friuli a.o.), and a very large number of factor IX variants. During the last 2 years about 180 pedigrees with hemophilia B have been found to have an abnormal factor IX molecule (hemophilia B+, CRM-positive, CRM-reduced). Whether the properties of all these factor IX variants are different cannot be established at this moment. Because specific immunologic assays for factors II, VII, IX and X have become widely available, it can be expected that many additional variants will be detected in the near future. At present detailed knowledge on the mechanism of action of the vitamin K de2