Missense Mutations at ALA-10 in the Factor IX Propeptide: A Novel Mechanism for Severe Bleeding During Oral Anticoagulant Therapy

Summary

Bleeding complications represent the most common and unwanted side effect of oral anticoagulant therapy. We present a novel mechanism for bleeding during coumarin therapy, attributed to newly described missense mutations in the factor IX propeptides of three patients. Strikingly, bleeding occurred at therapeutic ranges of prothrombin time (PT) and international normalized ratio (INR). In all three patients, coumarin therapy caused an unusually selective decrease of factor IX activity (below levels of 1%–3%). Upon withdrawal of coumarin, factor IX activity increased to subnormal or normal values of 48%, 83% and 125%, respectively. Analysis of the factor IX gene revealed two different missense mutations affecting the Ala-io residue in the propeptide coding region: Ala[GCC] to Val[GTC] in two patients and Ala[GCC] to Thr[ACC] in one patient. Screening 115 random blood donors for mutations at Ala-10, no further mutation could be detected, thus excluding a frequent polymorphism at this position. The mutation in the factor IX propeptide at a position, which is essential for the carboxylase recognition site, probably causes a reduced affinity of the carboxylase enzyme to the propeptide. This effect leads to an impaired carboxylase epoxidase reaction that is decisively triggered by the vitamin K concentration. As a clinical consequence of our findings, determination of Factor IX and APTT additionally to PT and INR is recommended in coumarin-treated patients with an uncommon bleeding pattern.