Non‐fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX

Abstract

Summary. Background and objectives: The key complication of treatment with vitamin K antagonists (VKAs) is bleeding. The major determinant of VKA-induced bleeding is the intensity of anticoagulation. Individual patient characteristics may also influence bleeding risk. In addition, soluble thrombomodulin (s-TM) levels and mutations in the propeptide of factor (F)IX are important candidate risk factors in this respect. Patients and methods: A matched casecontrol study was designed to search for risk factors that predict bleeding during VKA treatment. We selected cases that had experienced major bleeding during treatment with VKA and matched controls without bleeding complications from the databases of two Thrombosis Services. The controls were matched for indication of treatment, age, gender, type of anticoagulant used and whether or not treatment with VKA was stopped. DNA and plasma were stored of all cases and controls. Results and conclusions: In total 110 patients and 220 controls consented to participate. The results indicate that s-TM levels, measured by ELISA, may be a risk indicator for bleeding [crude odds ratio 3.25 for the highest quartile vs. the lowest quartile (95% confidence interval 1.40, 7.51)]. Three novel mutations, determined by direct sequencing, in the gene portion encoding the propeptide of FIX were identified that do not seem to play an important role in bleeding risk during treatment with VKAs.

Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study

“…An association with major haemorrhage was also seen with the factor V gene; although this association is biologically plausible, the effect size was small. Bleeding with warfarin has also previously been related to factor IX polymorphisms [45,46]; although there was no association with bleeding in our patients, there was a significant association with time to therapeutic INR ( Table 3).…”

A C1173T Dimorphism in the VKORC1 Gene Determines Coumarin Sensitivity and Bleeding Risk

“…For the present analyses we used DNA from a previously reported case-control study [6]. This study includes 110 patients classified as “severe bleeders” and 220 “non-bleeders” (more than 96% of the participants are Caucasian) who were selected from two anticoagulation clinics.…”

Pharmacogenetics of warfarin: current status and future challenges

“…83,96,101 Mutations in the propeptide of F9, causing a change from alanine to valine or threonine at residue À10, lead to a rapid drop in factor IX during warfarin treatment and are the reason for bleeding in rare cases. 102,103 Promoter polymorphisms and a synonymous coding polymorphism in exon 7 of F10 have also been studied, but no effect on warfarin sensitivity was seen. 83,96 Unlike other vitamin K-dependent factors, protein C and S work as natural anticoagulants.…”