Paediatric venous thromboembolism: a report from the Italian Registry of Thrombosis in Children (RITI).

BACKGROUND: The Italian Registry of Thrombosis in Children (RITI) was established by a multidisciplinary team with the aims of improving knowledge about neonatal and paediatric thrombotic events in Italy and providing a preliminary source of data for the future development of specific clinical trials and diagnostic-therapeutic protocols. MATERIALS AND METHODS: We analysed the subset of RITI data concerning paediatric systemic venous thromboembolic events that occurred between January 2007 and June 2013. RESULTS: Eighty-five deep venous thromboses and seven pulmonary emboli were registered in the RITI. A prevalence peak was observed in children aged 10 to 18 years and, unexpectedly, in children aged 1 to 5 years. A central venous line was the main risk factor (55% of venous thromboembolic events); surgery (not cardiac) (25%), concomitant infections (23%) and malignancy (22%) were the clinical conditions most often associated with the onset of venous thromboembolism. There was a diagnostic delay of more than 24 hours in 37% of the venous thromboembolic events. Doppler ultrasound was the most widely used test for the objective diagnosis of deep venous thrombosis (87%). Antithrombotic therapy was administered in 96% of venous thromboembolic events, mainly low molecular weight heparin (60%). In 2% of cases recurrences occurred, while post-thrombotic syndrome developed in 8.5% of cases. DISCUSSION: Although the data from the RITI are largely in agreement with published data, peaks of prevalence of thrombosis, risk factors and objective tests used for the diagnosis showed some peculiarities which may deserve attention.

Evaluation of the prevalence of severe hyperhomocysteinemia in adult patients with thrombosis who underwent screening for thrombophilia.

INTRODUCTION: Treatment with B-vitamins and betaine reduces the high risk of thrombosis in patients with homocystinuria, a metabolic syndrome that is characterized by severe hyperhomocysteinemia (HHcy). In contrast, there is no clear demonstration that B-vitamins reduce the risk of thrombosis in patients with mild HHcy: for this reason, many question the clinical utility of measuring total Hcy (tHcy) in patients with thrombosis. However, thrombosis may be the first clinical manifestation of homocystinuria in patients reaching adulthood without signs and symptoms of the syndrome. AIM: 1) to measure the prevalence of severe, previously undiagnosed, HHcy among patients with thrombosis 2) to profile these patients on the basis of their characteristics. METHODS: Six Italian Thrombosis Centers completed a first questionnaire, reporting tHcy levels in patients with thrombosis who underwent thrombophilia screening, and a second questionnaire, reporting the characteristics of patients with severe HHcy (tHcy>100µmol/L). RESULTS: Of 19,678 cross-sectionally collected patients with thrombosis who underwent thrombophilia screening in the last 12.5years (median value, range 6-17), 38 had severe HHcy (0.2%). Their median age at diagnosis was 47years (range 19-83) and the median level of tHcy was 130µmol/L (range 101-262). Venous thromboembolism (71%) was more frequent than arterial thromboembolism (26%); recurrent thrombosis occurred in 42% of cases. CONCLUSIONS: Measurement of tHcy in adult patients with thrombosis may reveal the presence of severe HHcy. Since treatment of patients with severe HHcy decreases the risk of thrombosis, measurement of tHcy in patients with thrombosis may prove clinically useful.

Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy.

INTRODUCTION: Anticoagulants of the coumarin type are effective drugs for the treatment and prevention of thromboembolic diseases. However, they have a narrow therapeutic range and show inter- and intra-individual variability in dose requirement, largely conditioned by both environmental and genetic factors. METHODS: This prospective study investigated, during the initial phase of acenocoumarol therapy, the effect of CYP2C9 variant alleles and VKORC1 haplotypes, single and in combination, in 220 Italians. RESULTS: CYP2C9*3 was associated with a 25% dose reduction and an increased risk of over-anticoagulation (International Normalized Ratio [INR] > 6) on day 4. Two copies of the VKORC1*2 haplotype were associated with a 45% dose reduction and an increased risk of over-anticoagulation. Homozygosity for VKORC1*3 and VKORC1*4 was associated with an increased dose requirement and a reduced risk of over-anticoagulation. The VKORC1*3 or *4 plus CYP2C9*1 genotype combination was associated with the highest dose requirement and the lowest INR on day 4; VKORC1*2 plus CYP2C9*3 was associated with the lowest dose requirement, the highest INR and an increased risk of over-anticoagulation. Even though they spent approximately 50% of the time within the target therapeutic range, VKORC1*3 or *4 plus CYP2C9*1 carriers spent a large percentage of the remaining time below and carriers of VKORC1*2 plus CYP2C9*3 above the target range. DISCUSSION: The determination of VKORC1*3 and VKORC1*4 haplotypes may be an important addition to CYP2C9 and VKORC1*2 genotyping to identify patients at risk of being outside the target range during initial anticoagulation with acenocoumarol.