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PubMed2004

Overanticoagulation associated with combined use of lactulose and acenocoumarol or phenprocoumon.

Some medical textbooks on drug interactions take note of the potential interaction between laxatives and coumarin anticoagulants, but epidemiological evidence that this interaction is of practical importance is lacking. We conducted a follow-up study in a large population-based cohort to investigate which laxatives are associated with overanticoagulation during therapy with coumarins. Of the 1124 patients in the cohort, 351 developed an International Normalized Ratio > or = 6.0. The only laxative with a moderate but significantly increased relative risk of overanticoagulation was lactulose (relative risk 3.4, 95% confidence interval 2.2, 5.3). In view of the widespread use of lactulose, especially among the elderly, awareness of this potential drug interaction is required.

Acenocoumarol↗
PubMed2001

[An uncommon cause of severe soft tissue bleeding during phenprocoumon treatment].

HISTORY AND ADMISSION FINDINGS: A 66-year-old patient presented to our clinic with extensive left arm and left flank haematomas, anaemia, a prolonged activated partial thromboplastin time (aPTT), and reduced factor IX activity 6 weeks after prosthetic mechanical aortic valve implantation. INVESTIGATION: Treatment with both vitamin K and a single injection of factor IX concentrate led to normalization of the activated partial thromboplastin time and factor IX activity, which remained constant for several days. No acquired factor IX inhibitor was detectable. Analysis of exon 2 of the factor IX gene revealed a C-->T mutation in codon 10 of the propeptide region, resulting in the substitution of alanine by valine. Echocardiography revealed a significant paravalvular leak. TREATMENT AND COURSE: The substitution of valine for alanine in the factor IX propeptide leads to an impaired affinity of factor IX to the vitamin K-carboxylase complex. In this situation, treatment with coumarin derivatives can profoundly reduce factor IX activity and result in severe bleeding episodes. This patient was re-exposed to warfarin under close hematological monitoring. After 4 days factor IX activity had decreased to 15%, which was associated with an increase of the aPTT and a mild decrease of the prothrombin time. Due to rapid progression of the paravalvular leak and almost impossible long-term orale anticoagulation with coumarin derivatives, we recommended replacement of the prosthetic mechanical valve with a biological device. CONCLUSION: The development of severe bleeding in the context of initiating warfarin therapy raises the suspicion of a factor IX propeptide mutation. The initial screening test is the activated partial thromboplastin time, which is elevated in the presence of the mutation. If concomitantly diminished factor IX activity is found the factor IX propeptide mutation should be excluded. Use of lifelong coumarin derivatives is contraindicated in patients with this mutation. However, a general screening of the activated partial thromboplastin time after coumarin initiation is not justified by cost/benefit analysis.

Aged↗
PubMed1979

The binding of phenprocoumon to human plasma proteins.

By in vitro experiments with equilibrium dialysis and 5 micrograms PPC per ml an average of 99.7 +/- 0.2% was bound to serum proteins. The binding in a solution with the albumin concentration which was present in the serum samples did not differ from this binding or from the binding in plasma where coagulation was prevented with either heparin or citrate. The binding constant in albumin solutions at 37 degrees was 4.5 +/- 0.31/mol x 10(-5) and an average of 1.16 +/- 0.04 primary binding sites was found. The association constant for the PPC albumin interaction was temperature dependent and the results of thermodynamic calculations suggested a combined ionic and non-polar type of binding as the change in enthalpy contributed with 40% of change in free energy. A large positive entropy change was found (15.79 Kcal/mol/degree K). The addition of phytomenadione to albumin solutions and of menadione to plasma caused a considerable decrease in the protein bound fraction of PPC, indicating the relevance of a study concerning the possible clinical consequences of these interactions.

4-Hydroxycoumarins↗