Life threatening bleeding under adequate oral anticoagulation

Summary

We report on two men with severe and recurrent bleeding episodes under well performed phenprocoumon therapy. Both patients showed an INR value within the therapeutic/subtherapeutic range with an inappropriately prolonged activated partial thromboplastin time (aPTT). The vitamin K-dependent coagulation factors were in the expected range, except for factor IX, which was as low as in moderate haemophilia B. After substitution of vitamin K, factor IX and the aPTT recovered completely in one case. In the other case factor IX was not measured but aPTT normalized. Diagnosis of an increased sensitivity of factor IX to phenprocoumon was assumed and proven in both cases by the demonstration of a missense mutation at ALA-10 in the factor IX propeptide.

Zusammenfassung

Wir berichten über zwei Patienten mit schwerer Blutungsneigung unter gut eingestellter oraler Antikoagulation. Bei beiden Patienten fiel bei therapeutischem bzw. subtherapeutischem INR eine disproportional verlängerte aPTT auf. Außer Faktor IX, der Werte entsprechend einer mittelschweren Hämophilie B aufwies, waren alle Vitamin-K-abhängigen Faktoren im erwarteten Bereich. Nach Substitution von Vitamin K normalisierten sich sowohl der Faktor IX als auch die aPTT prompt bei Patient 1, bei Patient 2 wurde nur die Normalisierung der aPTT dokumentiert. In beiden Fällen wurde ein Faktor IX mit erhöhter Empfindlichkeit auf Vitamin-K-Mangel angenommen. Dies wurde mit dem Nachweis einer Missense-Mutation Ala-10 im Faktor-IX-Propeptid bewiesen.

Keywords

Oral anticoagulation - bleeding - factor IX propeptide mutation

Schlüsselwörter

Orale Antikoagulation - Blutung - Faktor-IX-Propeptidmutation

• References

• 1 Carlisle TL, Suttie JW. Vitamin K dependent carboxylase: subcellular localization of the carboxylase and enzymes involved in vitamin K metabolism in rat liver. Biochemistry 1980; 19: 1161.
• 2 Chu K, Wu SM, Stanley T, Stafford DW, High KA. A mutation in the propeptide of factor IX leads to warfarin sensitivity by novel mechanism. J Clin Invest 1996; 98: 1619-25.
• 3 Fasco MJ, Hildebrandt EF, Suttie JW. Evidence that warfarin anticoagulant action involves two distinct reductase activities. J Biol Chem 1982; 257: 11210-2.
• 4 Jorgensen MJ, Cantor AB, Furie BC, Furie B. Recognition site directing vitamin K-dependent γ-carboxylation resides on the propeptide of factor IX. Cell 1987; 48: 185-91.
• 5 Oldenburg J, Quenzel EM, Harbrecht U, Fregin A, Kress W, Muller CR, Hertfelder HJ, Schwaab R, Brackmann HH, Hanfland B. Missense mutation at Ala-10 in the factor IX-propeptide: an insignificant variant in normal life but a decisive cause for bleeding during oral anticoagulant therapy. Br J Haematol 1997; 98: 240-4.
• 6 Oldenburg J, Kriz K, Wuillemin WA, Maly FE, von Felten A, Siegemund A, Keeling DM, Paker P, Chu K, Konkle BA, Lämmle B, Albert T. Genetic predisposition of bleeding during oral anticoagulant therapy: Evidence for common founder mutations (FIX Val-10 and FIX Thr-10) and an independent CpG hotspot mutation (FIX Thr-10). Thromb Haemost 2001; 85: 454-7.
• 7 Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berretini M, Musolesi S. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423-8.
• 8 Peters J, Luddington R, Brown K, Baglin C, Baglin T. Should patients starting anticoagulant therapy be screened for the missense mutations at Ala-10 in the factor IX propeptide?. Br J Haematol 1997; 99: 467-8.
• 9 Soute BA, Ulrich MM, Watson AD, Maddison JE, Ebberink RH, Vermeer C. Congenital deficiency of all vitamin K-dependent blood coagulation factors due to a defective vitamin K-dependent carboxylase in Devon Rex cats. Thromb Haemost 1992; 57: 521-5.
• 10 Willingham AK, Matschiner JT. Changes in phylloquinone epoxidase activity related to prothrombin synthesis and microsomal clotting activity in the rat. Biochem J 1974; 140: 435-41.