Paediatric arterial ischaemic stroke and cerebral sinovenous thrombosis. First report from the Italian Registry of Pediatric Thrombosis (R. I. T. I., Registro Italiano Trombosi Infantili).

Data from large case series of children with cerebral thrombotic events are pivotal to improve prevention, early recognition and treatment of these conditions. The Italian Registry of Pediatric Thrombosis (R. I. T. I.) was established in 2007 by a multidisciplinary team, aiming for a better understanding of 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. We analysed data relative to the paediatric cerebral thrombotic events of the R. I. T. I. which occurred between January 2007 and June 2012. In the study period, 79 arterial ischaemic stroke (AIS) events (49 in males) and 91 cerebral sinovenous thrombosis (CSVT) events (65 in males) were enrolled in the R. I. T. I. Mean age at onset was 4.5 years in AIS, and 7.1 years in CSVT. Most common modes of presentation were hemiparesis, seizures and speech disturbances in AIS, and headache, seizures and lethargy in CSVT. Most common etiologies were underlying chronic diseases, vasculopathy and cardiopathy in AIS, and underlying chronic diseases and infection in CSVT. Time to diagnosis exceeded 24 hours in 46 % AIS and 59 % CSVT. Overall data from the Italian Registry are in substantial agreement with those from the literature, despite small differences. Among these, a longer time to diagnosis compared to other registries and case series poses the accent to the need of an earlier recognition of paediatric cerebrovascular events in Italy, in order to enable prompt and effective treatment strategies.

Prevalence of inherited thrombophilia in patients with documented stent thrombosis.

BACKGROUND: Stent thrombosis (ST) is a multi-factorial process involving different mechanisms. The impact of inherited coagulation disorders in the genesis of ST has never been assessed. The aim of the present study was to evaluate the prevalence of G1691A Factor V Leiden mutation, G20210A Factor II (prothrombin) mutation and C677T homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism in patients with ST. METHODS AND RESULTS: The prevalence of the aforementioned gene variations was assessed in 127 patients: 50 admitted for ST and 77 previously treated with percutaneous coronary intervention not developing ST. A control cohort of 529 healthy volunteers was sampled from the same geographical area. Patients with ST were carriers of at least 1 gene variation in 28% of cases. The prevalence of G1691A Factor V Leiden mutation (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.04-10.5), G20210A Factor II mutation (OR=0.63; 95% CI: 0.12-3.28) and C677T MTHFR homozygous polymorphism (OR=1.13; 95% CI: 0.47-2.72) did not differ significantly among patients with or without ST. The logistic regression model did not show a significant association between gene variations and ST (OR=0.61; 95% CI: 0.24-1.60; P=0.32). CONCLUSIONS: A specific association between studied gene variations and ST has not been detected. The relatively high prevalence of at least 1 gene anomaly in such a rare subset of patients, and its consequences in term of secondary prevention therapy, suggests that screening for thrombophilia might be justifiable in cases of ST.

Interaction between proatherosclerotic factors and right-to-left shunt on the risk of cryptogenic stroke: the Italian Project on Stroke in Young Adults.

OBJECTIVE: To explore the interaction effects between cardiac interatrial right-to-left shunt (RLS) and proatherosclerotic factors on the risk of brain ischaemia. DESIGN: Multicentre Italian case-control study. SETTING: University hospitals. PARTICIPANTS: 588 patients with cryptogenic stroke (CS) aged ≤45 years and 585 control subjects consecutively enrolled as part of the Italian Project on Stroke in Young Adults. METHODS: Interaction effects between RLS and an individual proatherosclerotic score computed from the number of conventional vascular risk factors for the risk of CS were investigated. Data were examined by logistic regression models and expressed as interaction OR or interaction risk difference (RD). RESULTS: CS risk increased with increasing number of proatherosclerotic factors in subjects without RLS (OR 2.73; 95% CI 1.98 to 3.76; RD +0.246; 95% CI +0.17 to +0.32; for subjects with one or more factors), but was higher in subjects with RLS and no additional proatherosclerotic factors (OR 5.14; 95% CI 3.49 to 7.58; RD +0.388; 95% CI +0.31 to +0.47) compared with subjects without RLS and no risk factors. Negative interaction and antagonistic effects between RLS and proatherosclerotic factors were observed (interaction OR 0.52; 95% CI 0.31 to 0.91; interaction RD -0.17; 95% CI -0.29 to -0.05). CONCLUSIONS: The influence of RLS on the risk of CS decreases with increasing number of atherosclerotic factors, and is highest when such factors are absent. Individual proatherosclerotic profiles may help to identify patients with CS whose patent foramen ovale is probably pathogenic.

Predictors of migraine subtypes in young adults with ischemic stroke: the italian project on stroke in young adults.

BACKGROUND AND PURPOSE: the mechanisms underlying the relationship between migraine and ischemic stroke remain uncertain. The aim of the present study was to investigate the predictive value of major cardiovascular risk factors, cardiac interatrial abnormalities, and additional biological markers on migraine subtypes in young adults with ischemic stroke. METHODS: ischemic stroke patients aged 45 years or younger were consecutively enrolled as part of the Italian Project on Stroke in Young Adults. A comprehensive evaluation was performed including assessment of self-reported migraine and cardiovascular risk factors, interatrial right-to-left shunt, and genotyping to detect factor V Leiden and the G20210A mutation in the prothrombin gene. RESULTS: nine hundred eighty-one patients (mean age, 36.0 ± 7.6 years; 50.7% women) were included. The risk of migraine with aura increased with decreasing number of cardiovascular risk factors (OR, 0.50; 95% CI, 0.24-0.99 for 2 factors or more), increasing number of thrombophilic variants (OR, 2.21; 95% CI, 1.05-4.68 for carriers of at least 1 of the 2), and the presence of right-to-left shunt (OR, 2.41; 95% CI, 1.37-3.45), as compared to patients without migraine. None of these factors had influence on the risk of migraine without aura. CONCLUSIONS: in young adults with ischemic stroke, low cardiovascular risk profile, right-to-left shunt, and an underlying procoagulant state are predictors of migraine with aura. The biological effects of these factors should be considered in future studies aimed at investigating the mechanisms linking migraine to brain ischemia.

Differences in the INR evaluation of two different thromboplastins in patients with positivity to lupus anticoagulant in ongoing oral anticoagulation.

BACKGROUND: A possible interference between lupus anticoagulant (LAC), a well characterized clotting inhibitor, in the International Normalized Ratio (INR) determination during oral anticoagulation (OA) has been reported in the literature. Few data are available about the relationship between this kind of interference and the daily clinical management of oral anticoagulation. The aim of the study is to evaluate the role of two different thromboplastins-RecombiPlasTin 2G and HepatoComplex-in the determination of INR values of several patients' ongoing OA for a previous thrombotic disorder with and without positivity to LAC, and to evaluate possible interferences in the daily therapeutic approach. PATIENTS AND METHODS: We selected 16 patients (13 females and 3 males, mean age 59 ± 16 years) with LAC positivity ongoing OA and 11 control subjects (7 females and 4 males, mean age 58 ± 14.5 years) with similar characteristics (ie, ethnic background and weight) with LAC negativity ongoing OA. 165 assays for INR determination were analyzed from both groups. Statistical analysis was performed using STATA 10 software. P values were considered significant if <0.05. RESULTS: Mean values of INR for patients with LAC positivity were 3.79 ± 1.63 when tested with RecombiPlasTin 2G vs 3.18 ± 1.15 when tested with HepatoComplex (P < 0.001, s); while mean values of INR for patients with antiphospholipid syndrome (APS) with LAC negativity were 3.54 ± 1.39 when tested with RecombiPlasTin 2G vs 3.23 ± 1.14 when tested with HepatoComplex (P < 0.002, s). An INR value > than 4.5 was found in 31/165 samples in 9 subjects, 8 patients with LAC positivity, and 1 control group subject with LAC negativity. There was a great difference in INR values in these subjects if we use the common thromboplastin (ie, RecombiPlasTin 2G) with a INR range varying from 5.14 ± 0.35 vs 3.79 ± 0.38 if we use another thromboplastin (ie, HepatoComplex) (P < 0.001, s). A change in the therapeutic approach for OA is possible in these cases because different INR values were obtained using different thromboplastins. DISCUSSION: Our data confirm that INR evaluation does not reveal significant changes also if tested with two different thromboplastins, for patients ongoing OA with and without LAC positivity, when the INR value is < than 4. Over this INR value there is a significant difference in patients with LAC positivity if we use a different thromboplastin for the INR determination. For this reason values obtained by RecombiPlasTin 2G need to be confirmed and matched with another thromboplastin (ie, HepatoComplex). This approach may be useful in order to have a good INR testing for the chronic long-term treatment with OA in particular in patients with LAC positivity.

Is there a relationship between factor V Leiden and type 2 diabetes?

BACKGROUND: Diabetes is well known risk factor for thrombotic events. The association between diabetes and venous thromboembolism is still matter of debate. However, during diabetes an acquired thrombophilia is present and is due to the non-enzymatic glycosilation of clotting inhibitors as antithrombin thus leading to hypercoagulable state. A possibile relationship between the presence of FVL gene variant in type 1 or type 2 diabetes has been hypothysed by several reports in the Literature with non-univocal findings. PATIENTS AND METHODS: Retrospectively we analysed nearly 7000 patients referred to our Thrombosis Center for venous thromboembolism (VTE) then we selected 115 patients underwent to the screening for inherited thrombophilia. All selected patients were divided in 2 groups: the first group (group A) included 64 patients with previous VTE and carriers of factor V Leiden, while the second group (group B) included 51 patients with previous VTE and evetually carriers of thrombophilic defects other than factor V Leiden. Patients of group B acted as control group. 75 g oral glucose tolerance Test (OGTT) recommended by WHO was perfomed to all subjects in the study in order to screen subjects with glucose reduced tolerance or subjects with inducible diabetes. Statistical analysis was performed with STATA 6 http://www.stata.com with Student t test for unpaired data, with chi2 test or with Fisher exact test where appropriated; differences were considered to be significant if p < 0.05. RESULTS: We did not find sifferences between glycaemia at baseline and after OGTT between patients with VTE carriers of FVL compared to non-carriers of FVL. We found a relevant increase in the prevalence of IGT and diabetes between patients with VTE carriers of FVL compared to non-carriers of FVL although this increase did not raise statistical significance. DISCUSSION: our data pointed out an interesting aspect of the linking between FVL gene variant, diabetes and atherothrombosis and other vascular complications, although data on larger population are needed; this aspect may be another relevant topic of research based because also a link between the pathogenesis of venous thrombosis and atherothrombosis has been recently reported in the Literature.

Intima-media thickness evolution after treatment with infliximab in patients with rheumatoid arthritis.

BACKGROUND: Atherosclerosis is a well known progressive disease that recognizes risk factors such as diabetes, hypertension, smoking, dyslipidemia, and inflammation. Mechanisms underlying atherosclerotic processes during inflammation are not completely understood, but cytokines are also involved, in particular tumor necrosis factor-alpha (TNF-alpha). Chronic inflammatory diseases such as rheumatoid arthritis (RA) are commonly associated with atherosclerotic complication. Little is known about the role of treatment of chronic inflammatory disease on the evolution of atherosclerosis in this kind of disease. Usually, evolution of atherosclerosis is monitored by intima-media thickness and the presence of plaques on several arteries such as common carotid. AIM: The aim of the study was to monitor atherosclerosis evolution in seven RA patients on common treatment with infliximab (an anti-TNF-alpha drug) compared with seven RA patients during common treatment but not treated with infliximab. PATIENTS AND METHODS: We selected 14 patients with RA according to the American College of Rheumatology classification criteria. Seven patients were selected before and after common treatment for RA based on nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, and steroids (12 months), and seven patients before and after treatment based on infliximab associated with NSAIDs, methotrexate, and steroids (12 months). Ultrasound vascular imaging was performed to screen intima-media thickness and the presence of atherosclerotic plaques on common carotid artery and identify evolution of atherosclerosis. RESULTS: After 12 months, patients that were treated with infliximab showed significant worsening of atherosclerosis with an increase of intima-media thickness and the presence of further atherosclerotic plaques compared to patients that were treated traditionally and showed a nonsignificant increase of the same parameters. DISCUSSION: Treatment based on anti-TNF-alpha such as infliximab shows a worsening evolution of atherosclerosis based on our data. If these data are associated with a poor clinical outcome such as atherothrombosis of cerebral vessels and/or coronary vessels, this should be evaluated by further studies.

Homocysteine, MTHFR C677T gene polymorphism, folic acid and vitamin B 12 in patients with retinal vein occlusion.

BACKGROUND: Many available data have suggested that hyperhomocysteinaemia, an established independent risk factor for thrombosis (arterial and venous), may be associated with an increased risk of retinal vein occlusion (RVO). AIM OF THE STUDY: To evaluate homocysteine metabolism in consecutive caucasian patients affected by RVO from Northern Italy. PATIENTS AND METHODS: 69 consecutive patients from Northern Italy (mean age 64.1 +/- 14.6 yy) with recent RVO, were tested for plasma levels of homocysteine (tHcy: fasting and after loading with methionine), cyanocobalamine and folic acid levels (CMIA-Abbot) and looking for MTHFR C677T mutation (Light Cycler-Roche) and compared to 50 volunteers, enrolled as a control group. RESULTS: Fasting levels of tHcy were significantly higher in patients than in controls: mean value 14.7 +/- 7.7 vs 10.2 +/- 8 nmol/ml. Post load levels were also significantly higher: mean value 42.7 +/- 23.7 vs 30.4 +/- 13.3 nmol/ml; Total homocysteine increase was also evaluated (i.e. Delta-tHcy) after methionine load and was also significantly higher in patients compared to control subjects: mean Delta-tHcy 27.8 +/- 21.5 vs 21.0 +/- 16 nmol/ml (normal value < 25 nmol/ml). Furthermore, patients affected by RVO show low folic acid and/or vitamin B12 levels, although differences with control group did not reach statistical significance. Heterozygous and homozygous MTHFR mutation were respectively in study group 46% and 29% vs control group 56% and 4%. CONCLUSION: our data confirm that hyperhomocysteinaemia is a risk factor for RVO, and also that TT genotype of MTHFR C677T is more frequently associated with RVO: if the mutation per se is a risk factor for RVO remains an open question to be confirmed because another study from US did not reveal this aspect. Hyperomocysteinemia is modifiable risk factor for thrombotic diseases. Therefore, a screening for tHcy plasma levels in patients with recent retinal vein occlusion could allow to identify patients who might benefit from supplementation with vitamins and normalization of homocysteine levels, in fasting and after methionine load.