No impact of factor IX Ala-10 mutations in acenocoumarol-treated southern Europeans

Abstract

Increased risk of bleeding during oral anticoagulant (OA) treatment may be related to mutations in the precursor of coagulation factor IX. Missense mutations at Ala-10 (Ala-10Thre and Ala-10Val) in the factor IX propeptide lead to impaired carboxylation of factor IX. When patients carrying these mutations are treated with coumarins, functional factor IX levels decrease significantly, leading to an excessively prolonged activated partial thromboplastin time (aPTT) and an increased bleeding risk. Mutations at Ala-10 have been described in northern-European patients, but it is not known whether geographical differences play a role in the prevalence of these mutations. We aimed to analyze the prevalence of mutations at Ala-10 in factor IX in southern-European patients on OA treatment. Patients attending the Oral Anticoagulant Unit of the Hospital Clinic were prospectively included. The aPTT was determined at their normal International Normalized Ratio (INR) control. When the aPTT was excessively prolonged for the INR value, determination of factor IX and genotyping for Ala-10 mutations was performed. A total of 2360 patients were included (1289 men, 1071 women; mean age, 70.5 +/- 12.1 years). Twenty-four patients (16 men, eight women; mean age, 61.0 +/- 16.2 years) had an aPTT over that expected for the INR. The mean aPTT was 69.6 +/- 16.2 s. Only one patient presented with a factor IX level lower than 10%. None of the 24 patients carried mutations at Ala-10. Mutations at Ala-10 in factor IX were non-existent in the southern-European population analyzed, and thus, do not represent a relevant cause of bleeding during OA treatment.

3-{2-[2-(Diphenylmethylene)hydrazinyl]thiazol-4-yl}-2H-chromen-2-one

“…For applications of coumarin derivatives, see: Tassies et al (2002); Laffitte et al (2002); Weber et al (1998) ;Finn et al (2004); Kimura et al (1985). For applications of aminothiazoles derivatives, see: Hiremath et al (1992); Karah et al (1998); Jayashree et al (2005).…”

“…Coumarin derivatives having pronounced biological activities are used as anticoagulants (Tassies et al, 2002), antibacterial (Laffitte et al, 2002), cytotoxic (Weber et al, 1998), free radical scavengers (Finn et al, 2004) and enzyme inhibiting (Kimura et al, 1985) agents. Moreover, aminothiazoles derivatives have been reported to exhibit significant antifungal (Hiremath et al, 1992), anti-tuberculosis (Karah et al, 1998) and anti-inflammatory (Jayashree et al, 2005) activities.…”

(E)-1-[1-(6-Bromo-2-oxo-2H-chromen-3-yl)ethylidene]thiosemicarbazide

“…Thiosemicarbazide compounds exhibit various biological activities such as anti-bacterial, anti-fungal and especially antituberculosis . Apart from this, coumarins constitute an important class of compounds found throughout the plant kingdom and are known to have diverse activities such as anti-coagulants (Anderson et al, 2002, Tassies et al, 2002, anti-bacterial (Mitscher, 2002, Laffitte et al, 2002, anti-fungal (Moffett, 1964) and cytotoxicity (Weber et al, 1998) properties. The coumarin moiety and related derivatives are also reported to have importance as vasodilators (Hoult & Payá, 1996), anti-mutagenic agents (Pillai et al, 1999), scavengers of reactive oxygen species (Finn et al, 2004), as well as lipoxygenese and cyclooxygenese inhibitors (Kimura et al, 1985, Hofmanová et al, 1998.…”

“…For general background to and applications of the title thiosemicarbazide compound, see: Anderson et al (2002); Chulian et al (2009); Desai et al (1984); Finn et al (2004); Hofmanová et al (1998); Hoult & Payá (1996); Kimura et al (1985); Laffitte et al (2002); Mitscher (2002); Moffett (1964); Pillai et al (1999); Shukla et al (1984); Tassies et al (2002); Weber et al (1998). For the preparation, see: Moamen et al (2009).…”

Life-threatening bleeding under vitamin K antagonists in spite of an INR in the therapeutic range

“…Systematic screening in 4039 individuals yielded no further case [4,[18][19][20]. Therefore, prevalence of Ala-10Thr or Ala-10Val variants in the population is estimated to range from 1/1,000 to 1/10,000 and systematic screening prior to initiating oral anticoagulation is not indicated.…”