MISSENSE MUTATIONS AT ALA-10 IN THE FACTOR-IX PROPEPTIDE - AN INSIGNIFICANT VARIANT IN NORMAL LIFE BUT A DECISIVE CAUSE OF BLEEDING DURING ORAL ANTICOAGULANT-THERAPY

Bleeding complications are the most common and unwanted side-effect of oral anticoagulant therapy. We report three patients in whom mutation s in the factor IX (FLX) propeptide were found to cause severe bleedin g during coumarin therapy. Striking, the bleeding occurred within the therapeutic ranges of the prothrombin time (PT) and international norm alized ration (INR). In all three patients coumarin therapy caused an unusually selective decrease of FIX activity (FIX:C) to levels below 1 -3%. Upon withdrawal of coumarin, FIX:C increased to subnormal or norm al values of 55%, 85% and 125%, respectively. Analysis of the FIX gene revealed two different missense mutations affecting the Ala-10 residu e in the propeptide coding region: Ala[GCC] to Val[GTC] in two patient s and Ala[GCC] to Thr[Acc] in one patient. No further mutation was det ected by screening 195 random blood donors for mutations at Ala-10, th us excluding a frequent polymorphism at this position. The mutation in the FIX propeptide at a position which is essential for the carboxyla se recognition site causes a reduced affinity of the carboxylase enzym e to the propeptide. This effect leads to an impaired carboxylase epox idase reaction which is decisively triggered by the vitamin K concentr ation. Determination of FIX and APTT in addition to PT and INR is ther efore recommended in coumarin-treated patients with an uncommon bleedi ng pattern.