V. Morelli

A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease

We assessed the effect of a recently described mutation in the MTHFR gene (1298 A → C) on the risk of deep venous thrombosis (DVT) by determining its prevalence in 190 patients with verified DVT and in age‐, race‐ and gender‐matched controls. MTHFR 1298 A → C was found in 42.1% of patients and in 41.1% of controls. The OR for venous thrombosis was 1.07 (95% CI 0.70–1.65) for heterozygotes and 0.83 (95% CI 0.33–2.08) for homozygotes. The OR for the factor V Leiden (FVL) mutation was 3.40 (95% CI 1.22–9.48), for FII 20210 G → A was 5.22 (95% CI 1.12–24.2) and for MTHFR 677 C → T, 1.24 (95% CI 0.82–1.87). No significant increased risk for venous thrombosis was found when MTHFR 1298 A → C was coinherited with FVL (OR 2.85, 95% CI 0.88–9.23), FII 20210 G → A (OR 7.19, 95% CI 0.87–59.4) or MTHFR 677 C → T (OR 1.44, 95% CI 0.71–2.92). These data do not support a critical role of MTHFR 1298 A → C in the predisposition to DVT.

Tuberculosis: an uncommon cause of cerebral venous thrombosis?

Several infectious etiologies are related to cerebral venous thrombosis (CVT), but a review of literature showed only few cases related to tuberculosis (TB), and only one with neurological manifestations. We report an unusual case of CVT related to TB and mutation in prothrombin gene. A 38-man black presented abrupt right hemiparestesis, and hemiparesis. Investigations revealed CVT. Cerebral spinal fluid (CSF) examination evidenced an infection by Mycobacterium. He was heterozygous for G20210A prothrombin mutation. Probably, hypercoagulability mechanisms of TB, added to mutation of prothrombin gene increase the risk of CVT.

The role of IL-6, IL-8 and MCP-1 and their promoter polymorphisms IL-6-174GC, IL-8-251AT and MCP-1-2518AG in the risk of venous thromboembolism: A case-control study

INTRODUCTION Cytokines increased the risk of venous thromboembolism (VTE) in some case-control studies, but not in a prospective study. Data concerning the role of cytokines in the risk of VTE are limited. We examined in a case-control study the association of VTE and levels of interleukin (IL)-6, IL-8 and monocyte chemotactic protein-1 (MCP-1) and assessed whether promoter polymorphisms (IL-6 -174GC, IL-8 -251AT, MCP-1 -2518AG) would affect the thrombotic risk and cytokine levels. MATERIALS AND METHODS The study included 119 patients (94 women) with a first event of VTE aged between 18-60 years, and 126 healthy controls (100 women) matched for age (±5 years). Blood was collected >7 months after the thrombotic event. Odds ratios (ORs) were calculated per increase of cytokines levels by 1 pg/mL. RESULTS ORs adjusted for age and sex were 1.520 [95% Confidence Interval (CI) 1.177 - 1.962] for IL-6, 1.095 (95% CI 1.002 - 1.196) for IL-8 and 1.000 (0.988 - 1.012) for MCP-1. With additional adjustment for ethnic composition, body mass index (BMI) and high sensitive C-reactive protein (hs-CRP), risk estimates remained significant for IL-6 and became of borderline statistical significance for IL-8. Polymorphisms did not influence the thrombotic risk and the cytokine levels in study participants. CONCLUSION VTE was associated with IL-6 and IL-8 levels, and for IL-6 this association was independent of BMI and hs-CRP. Thus far, a causal relationship between inflammation and VTE remains to be clarified and more prospective data are warranted.

Factor V Arg306 Thr (factor V Cambridge) and factor V Arg306 Gly mutations in venous thrombotic disease

We investigated the prevalence of two reported mutations of the factor V gene (factor V Arg306 → Thr, or factor V Cambridge, and factor V Arg306 → Gly) in 104 relatively young patients with verified venous thrombosis and in 208 age‐, sex‐ and race‐matched controls, in order to establish whether the two mutations are associated with increased predisposition for venous thrombosis. PCR amplification followed by BstNI and MspI digestion was employed to determine the genotypes, and each mutation was confirmed by DNA sequencing. Among the controls, one individual was found to be heterozygous for the factor V Arg306 → Thr mutation and one heterozygous for the factor V Arg306 → Gly mutation; none of the patients carried either mutation. Our findings do not support factor V Cambridge and factor V Arg306 → Gly as risk factors for venous thrombosis.

Tratamento da superdosagem de anticoagulantes orais

PURPOSE: To evaluate the response of 73 patients with antivitamin K (AVK) overdose to 3 different therapeutic regimens. METHODS: Seventy three patients were evaluated in 94 occasions: group A (N=32), consisted of drug withdrawal for 2 days followed by reduced dosage; group B (N=37), drug withdrawal and reassessment within 4 days; group C (N=25), oral administration of vitamin K. Therapeutic range was set between INR-values of 2 and 4. RESULTS: Reversal regimens did not result in differences among 61 patients who had initial INR 4, but 5 of them were bellow 4.5, without increased bleeding risk. There were 10 patients in group C bellow therapeutic range, 6 of them with INR < 1.6, with risk of thromboembolism. Thirteen patients bled, but none required transfusion. CONCLUSION: Reversal of excessive oral anticoagulation can be safely performed by initial withdrawal of the drug, followed by lower doses. Vitamin K administration may lead to INR bellow the therapeutic range. This should be reserved for patients with high INR or in the presence of bleeding.

Haplotypes of TAFI gene and the risk of cerebral venous thrombosis - a case-control study

INTRODUCTION Cerebral venous thrombosis (CVT) is an uncommon disease with some differences compared to other-site thrombosis, including a higher frequency in young people, female sex and oral contraceptive users. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a regulator of fibrinolysis, whose levels are genetically controlled and its increase is associated to thrombosis. Our objective was to investigate in a case-control study the association between CVT and TAFI single nucleotide polymorphisms (SNPs) and its haplotypes in comparison to other-site venous thrombosis and controls. MATERIALS AND METHODS Seventy two patients with CVT were compared to 143 individuals with no history of thromboembolic events (control group) and to 128 patients with deep vein thrombosis in the limbs and/or pulmonary embolism (venous thromboembolism-VTE group). SNPs were genotyped by restriction fragment length polymorphism or allele-specific PCR for F2 20210G>A, F5 1691G>A, TAFI (-1053C>T, -438G>A, 505G>A, 1040C>T and +1542C>G). RESULTS The GTC haplotype for TAFI 505G>A/1040C>T/+1542C>G SNPs was associated with an increased risk of CVT compared to controls [odds ratio (OR) 2.67, 95% confidence interval (CI): 1.13 - 6.34) and VTE group (OR 2.51, 95%CI: 1.07 - 8.06). The CVT risk became even more pronounced when evaluating unprovoked or hormone-related thrombosis cases: CVT compared to controls (OR 3.24, 95%CI: 1.19 - 8.82) and VTE group (OR 4.32, 95%CI: 1.27 - 14.63). CONCLUSIONS Our data indicate that the GTC haplotype for TAFI 505G>A/1040C>T/+1542C>G SNPs increased the risk of CVT in comparison to controls and VTE cases. Further studies are required to confirm our findings.