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Background: Our aim was to identify laboratory assays in order to assess the anticoagulant effects of dabigatran etexilate (DE). Methods: Twenty patients with nonvalvular atrial fibrillation treated on DE (110 mg per os twice daily) and 20 on acenocoumarol were studied. Conventional coagulation tests, endogenous thrombin potential (ETP), thromboelastometry (ROTEM), epinephrine-induced light transmission aggregometry (LTA), and Hemoclot Thrombin Inhibitors (HTI) were performed in all patients. Results: In ROTEM analysis, the lysis index at 60 minutes was significantly lower in patients receiving DE ( P = .011). In LTA, patients on DE showed decreased aggregation compared to those on acenocoumarol, marginally insignificant ( P = .068). Regarding ETP, acenocoumarol affected thrombin generation more than dabigatran (area under the curve [AUC], P < .001), while statistically significant associations were detected between dabigatran levels, as determined by the HTI assay, and almost all parameters of ETP assay (AUC, P < .001). Conclusion: The role of ETP in estimating anticoagulant activity of dabigatran possibly requires further research.

Background. The cost-effectiveness of universal leucoreduction of blood components remains unclear. When using leucoreduced red blood cells, the decrease in the rate of febrile non-haemolytic transfusion reactions (FNHTR) is the only proven, meaningful clinical benefit, whose relationship to costs can be calculated relatively easily. The aim of this study was to evaluate the cost-effectiveness of leucoreduction in avoiding FNHTR. Materials and methods. Data were obtained from two large tertiary hospitals in Athens, Greece, over a 4-year period (2009-2012). The incidence of FNHTR in patients transfused with leucoreduced or non-leucodepleted red blood cells, the additional cost of leucoreduction and the cost to treat the FNHTR were estimated. The incremental cost-effectiveness ratio (ICER), which is the ratio of the change in costs to the incremental benefits of leucoreduction, was calculated. Results. In total, 86,032 red blood cell units were transfused. Of these, 53,409 were leucodepleted and 32,623 were non-leucoreduced. Among patients transfused with leucodepleted units, 25 cases (0.047%) met the criteria for having a FNHTR, while in patients treated with non-leucoreduced components, 134 FNHTR were observed (0.411%). The ICER of leucoreduction was € 6,916 (i.e., the cost to prevent one case of FNHTR). Conclusions. Leucoreduction does not have a favourable cost-effectiveness ratio in relation to the occurrence of FNHTR. However, many factors, which could not be easily and accurately assessed, influence the long-term costs of transfusion. It is imperative to undertake a series of large, meticulously designed clinical studies across the entire spectrum of blood transfusion settings, to investigate most of the parameters involved. © SIMTI Servizi Srl. 12 2 232 237

Background: The circulating levels of plasminogen activator inhibitor type 1 (PAI-1) are increased in individuals carrying the 4G allele at position -675 of the PAI-1 gene. In turn, overexpression of PAI-1 has been found to affect both atheroma and thrombosis. However, the association between PAI-1 levels and the incidence of myocardial infarction (MI) is complicated by the potentially confounding effects of well-known cardiovascular risk factors. The current study tried to investigate in parallel the association of PAI-1 activity with the PAI-1 4G/5G polymorphism, with MI, and some components of metabolic syndrome (MetS). Methods: Using meta-analytical Mendelian randomization approaches, genotype-disease and genotype-phenotype associations were modeled simultaneously. Results: According to an additive model of inheritance and the Mendelian randomization approach, the MI-related odd ratio for individuals carrying the 4G allele was 1.088 with 95% confidence interval (CI) 1.007, 1.175. Moreover, the 4G carriers had, on average, higher PAI-1 activity than 5G carriers by 1.136 units (95% CI 0.738, 1.533). The metaregression analyses showed that the levels of triglycerides (p =0.005), cholesterol (p=0.037) and PAI-1 (p =0.021) in controls were associated with the MI risk conferred by the 4G carriers. Conclusions: The Mendelian randomization meta-analysis confirmed previous knowledge that the PAI-1 4G allele slightly increases the risk for MI. In addition, it supports the notion that PAI-1 activity and established cardiovascular determinants, such as cholesterol and triglyceride levels, could lie in the etiological pathway from PAI-1 4G allele to the occurrence of MI. Further research is warranted to elucidate these interactions. 52 7 937 950

Background. The role of the D allele of the angiotensin-converting enzyme (ACE) gene I/D polymorphism in the clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains controversial. Our aim was to assess simultaneously the effect of the ACE I/D polymorphisms as well as the serum and BALF ACE levels on prognosis of patients with ARDS. Methods. Sixty-nine mechanically ventilated patients with ALI/ARDS were recruited. ACE activity levels both in serum and BALF were assessed by chemical methods. Patients were genotyped for ACE I/D polymorphisms. Time-to-event analysis evaluated the variables associated with the 28-day and 90-day mortality. Finally, we performed a meta-analysis of studies examining the association between ACE I/D polymorphisms and mortality of ALI/ARDS patients. Results. In the multivariable model, age, lung compliance, serum lactate and serum ACE levels were significantly associated with both 28- and 90-day mortality. No significant correlation was found between serum and BALF ACE levels (Spearman's rho=0.054; P=0.66). Serum ACE concentrations were significantly higher (P=0.046) in patients with D/D genotype versus the two other groups combined (I/D and I/I genotypes). The meta-analysis of 6 studies (including ours) provided evidence that D allele is significantly associated with increased mortality in ALI/ARDS patients, yielding a per-allele odds ratio of 1.76 (95% CI: 1.19, 2.59). Conclusion. Serum ACE levels appear to be affected by the I/D polymorphism and are correlated with prognosis in patients with ALI/ARDS indicating that further investigation of the clinical significance of the ACE in ARDS might be of value. 79 8 861 870

Essential thrombocythemia is characterized by persistent elevation and functional disturbances of platelets. Both the platelet function analyzer-100 (PFA-100) collagen-epinephrine (CEPI) cartridge and aggregometry with epinephrine are considered sensitive and valid methods in detecting abnormal platelet function in essential thrombocythemia. We attempted to confirm that restoration of abnormal platelet function results from platelet count reduction in essential thrombocythemia, by using these two methods. Thirty-nine essential thrombocythemia patients were divided into two groups on the basis of their platelet count. Group A participants (n = 20) exhibited platelet counts greater than 500 × 10 9/l, whereas group B participants (n = 19) had platelet counts below this limit. Hematological parameters, plasma von Willebrand factor (vWF) antigen and activity levels were assessed. Platelet function was analyzed by the PFA-100 and light transmission aggregometry with epinephrine, collagen, and ADP. The point mutation JAK2 V617F was identified and its effect on platelet function tests was also investigated. By using logistic regression analysis, white blood cell count, vWF activity level, and the measurements of aggregation in response to epinephrine were significantly different between the two groups. Epinephrine-induced aggregation retained the statistical significance in the multivariable procedure (P: 0.002). PFA-100 CEPI closure times were lower-but not statistically significant-in group B. Neither the JAK2 V617F positivity nor different cytoreductive treatments had any influence on ex-vivo platelet function tests. Our findings demonstrate normalization of platelet function resulting from platelet count reduction in essential thrombocythemia and reinforce the concept of lowering platelet counts in these patients. © 2011 Wolters Kluwer Health | Lippincott Williams &Wilkins. 22 6 457 462

Background. There is considerable evidence that elevated plasma homocysteine levels are associated with a prothrombotic milieu, whereas activation of the coagulation cascade is an important component of the pathogenesis of sepsis. The protein C pathway has been reported to play a central role both in the propagation of sepsis and a hyperhomocysteinemia-induced hypercoagulable state. Our primary aim was to measure plasma homocysteine levels in mechanically ventilated patients with severe sepsis/septic shock and to assess the association of these levels with relevant clinical outcomes. Methods. The study cohort included 102 mechanically ventilated patients with severe sepsis or septic shock. Demographics, comorbidities, clinical data and severity scores were recorded. Plasma homocysteine, vitamin B12, folate, creatinine, and protein C levels were measured in all study subjects upon enrollment, and genotyping for the C677T and A1298C polymorphisisms of the methylenetetrahydrofolate reductase (MTHFR) gene and for factor V Leiden (FVL) mutations was performed as well. The primary outcomes were mortality at 28 and 90 days; secondary outcomes included the number of days without renal or cardiovascular failure and the ventilator-free days during the study period. Results. Homocysteine levels were not significantly associated with any primary or secondary outcomes in the multivariable analysis. In addition, a synergistic effect of homocysteine with protein C levels was not detected. Conclusion. Our data suggest that plasma homocysteine levels may not inform the prognosis of mechanically ventilated patients with severe sepsis/septic shock. 76 10 787 794

Despite the considerable progress in antiretroviral therapy, the eradication of HIV-1 remains unfeasible. Therefore, novel agents are under investigation. The aim of this review is to summarize the conventional compounds, to describe the recently approved agents, and to take a comprehensive look at the clinically relevant findings of current research. © 2009 Bentham Science Publishers Ltd. 9 8 900 910

Plasminogen activator inhibitor (PAI-1), is the central component of the fibrinolytic system. A deletion/insertion (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been correlated with levels of plasma PAI-1. The 4G allele is associated with higher levels of PAI-1, and might increase the risk for intravascular thrombosis. However, the contribution of this genetic variant to the risk for thrombosis, both arterial and venous, has not been clearly established. A broad spectrum of findings regarding the effect of the 4G allele on thrombotic risk in different target organs has been reported. Our aim is to summarize the variable influence of this polymorphism on thrombotic events in different tissues or organs and explain the underlying mechanisms accounting for these differences. © 2007 Elsevier Ltd. All rights reserved. 122 6 736 742

The effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006.A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068-1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR: 1.833,95% CI: 1.325-2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered. © 2007 Schattauer GmbH, Stuttgart. 97 6 907 913

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Objective: To examine the secular trends of all AIDS opportunistic infections to occur first (Ols) in Greece, by year, by gender and by mode of transmission. Methods: The study included all AIDS defining conditions reported among Greek residents diagnosed with AIDS from 1981 to June 2003 and notified to the Hellenic Centre of Infectious Diseases Control. The analysis of trends in AIDS defining conditions in Greece has been performed only for the period 1993-2003. Results: From 1981 to the first six months of 2003, 2,394 AIDS cases, 2,361 adults and 33 children, have been reported. HIV wasting syndrome was the most frequent Ol to occur first followed by PCP pneumonia and Kaposi sarcoma. The frequency at which Ols occurred first varied by sex. Kaposi sarcoma was more frequent in males while tuberculosis and oesophageal candidiasis were more frequent in females. The frequency at which Ols occurred first varied also by exposure mode. Kaposi sarcoma was more frequent among men who have sex with men but that was not the case for the remaining transmission categories. From 1993 to the first six months of 2003 a downward trend was noticed only for chronic simplex disease. Since the introduction of HAART, an increasing trend was noticed for CMV disease, recurrent pneumonia, oesophageal candidiasis, Burkitt and immunoblastic lymphoma. Conclusion: Further epidemiological studies are needed to assess the Ols trends in coming years in order to plan prevention strategies and future medical care needs. 12 4 201 206

In Greece, HIV/AIDS surveillance is conducted by the Hellenic Centre for Infectious Diseases Control. The AIDS case reporting system was implemented in 1984, followed by notification of HIV infections in 1998. This article presents surveillance and trend analysis of paediatric HIV infection and AIDS, including cases identified prior to 1998. The number of HIV infected children in Greece is relatively low, raising to a cumulative total of 69 cases by June 2003, 44 (64%) of whom are thought to have been infected through mother-to-child transmission. Thirty three paediatric AIDS cases have been reported since the onset of epidemic, with Pneumonocystis carinii pneumonia being the most frequent opportunistic infection. A significant number of children in Greece were diagnosed after the age of 1 year. This could be attributed to the fact that many HIV-infected women are not identified during pregnancy, despite that fact that voluntary testing is available. It could also be attributed to the fact that data includes HIV infections collected retrospectively after 1998, and that foreign HIV-infected children may arrive in Greece at a later age. Furthermore, new paediatric HIV positive cases that were reported during the first half-year period of 2003 were foreign children born in eastern Europe and sub-Saharan Africa. Efforts should be made to identify women in these populations in time for proper intervention. HIV infection in children remains a huge problem worldwide, and it is very important to focus on reducing the risk of mother-to-child transmission. 9 9 9 11