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

• Published in: British journal of haematology Vol. 98; no. 1; pp. 240 - 244
• Main Authors: Oldenburg, Johannes, Quenzel, Ernst‐Markus, Harbrecht, Uschi, Fregin, Andreas, Kress, Wolfram, Müller, Clemens Rainer, Hertfelder, Hans‐Jörg, Schwaab, Rainer, Brackmann, Hans‐Hermann, Hanfland, Peter
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.07.1997; Blackwell
• Subjects: Administration, Oral; Adult; Aged; Anticoagulants - adverse effects; Biological and medical sciences; bleeding; Blood. Blood coagulation. Reticuloendothelial system; Exons - genetics; factor IX; Factor IX - genetics; Hemorrhage - chemically induced; Hemorrhage - genetics; Humans; Medical sciences; Mutation; mutations; oral anticoagulant therapy; Peptide Fragments - genetics; Pharmacology. Drug treatments; propeptide; Human; Nonsense mutation; Genetic variant; Metabolism toxicity relation; Oral administration; Anticoagulant; Hemorrhage; Chemotherapy; Factor IX; Treatment; Risk factor; Complication; Biosynthesis precursor; Coagulation factor
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.1997.2213036.x

Bleeding complications are the most common and unwanted side‐effect of oral anticoagulant therapy. We report three patients in whom mutations in the factor IX (FIX) propeptide were found to cause severe bleeding during coumarin therapy. Strikingly, the bleeding occurred within the therapeutic ranges of the prothrombin time (PT) and international normalized ratio (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 normal values of 55%, 85% and 125%, respectively. Analysis of the FIX gene revealed two different missense mutations affecting the Ala‐10 residue in the propeptide coding region: Ala[GCC] to Val[GTC] in two patients and Ala[GCC] to Thr[ACC] in one patient. No further mutation was detected by screening 195 random blood donors for mutations at Ala‐10, thus excluding a frequent polymorphism at this position. The mutation in the FIX propeptide at a position which is essential for the carboxylase recognition site causes a reduced affinity of the carboxylase enzyme to the propeptide. This effect leads to an impaired carboxylase epoxidase reaction which is decisively triggered by the vitamin K concentration. Determination of FIX and APTT in addition to PT and INR is therefore recommended in coumarin‐treated patients with an uncommon bleeding pattern.