Background-We have shown that normal D-dimer levels obtained after the discontinuation of oral anticoagulant treatment (OAT) has a high negative predictive value for recurrent venous thromboembolism (VTE). The aim of the present study was to assess the predictive value of D-dimer for recurrent VTE in subjects with a previous unprovoked event who are either carriers of inherited thrombophilia or not. Methods and Results-We prospectively evaluated 599 patients (301 males) with a previous VTE episode. They were repeatedly examined for D-dimer levels after OAT withdrawal and were screened for inherited thrombophilic alterations. Alterations were detected in 130 patients (21.7%), factor V Leiden (70 patients; 2 of whom were homozygotes) and prothrombin mutation (38 patients) were the most prevalent ones. Recurrent events were recorded in 58 subjects (9.7%) during a follow-up of 870.7 patient-years. Altered D-dimer levels at 1 month after OAT withdrawal were associated with a higher rate of subsequent recurrence in all subjects investigated, especially in those with an unprovoked qualifying VTE event (hazard ratio, 2.43; 95% confidence interval, 1.18 to 4.61) and in those with thrombophilia (hazard ratio, 8.34; 95% confidence interval, 2.72 to 17.43). The higher relative risk for recurrence of altered D-dimer was confirmed by multivariate analysis after adjustment for other risk factors. The negative predictive value of D-dimer was 92.9% and 95.8% in subjects with an unprovoked qualifying event or with thrombophilia, respectively. Conclusions-D-dimer levels measured 1 month after OAT withdrawal have a high negative predictive value for recurrence in subjects with unprovoked VTE who are either carriers or not carriers of congenital thrombophilia.

Although a number of studies have analysed so far the causes of death and the life expectancy in haemophilic populations, no investigations have been conducted among Italian haemophilia centres. Thus, the aim of this study was to investigate mortality, causes of deaths, life expectancy and co-morbidities in Italian persons with haemophilia (PWH). Data pertaining to a total of 443 PWH who died between 1980 and 2007 were retrospectively collected in the 30 centres who are members of the Italian Association of Haemophilia Centres that chose to participate. The mortality rate ratio standardized to the male Italian population (SMR) was reduced during the periods 1990-1999 and 2000-2007 such that during the latter, death rate overlapped that of the general population (SMR 1990-1999: 1.98 95% CI 1.54-2.51; SMR 2000-2007: 1.08 95% CI 0.83-1.40). Similarly, life expectancy in the whole haemophilic population increased in the same period (71.2 years in 2000-2007 vs. 64.0 in 1990-1999), approaching that of the general male population. While human immunodeficiency virus infection was the main cause of death (45%), 13% of deaths were caused by hepatitis C-associated complications. The results of this retrospective study show that in Italian PWH improvements in the quality of treatment and global medical care provided by specialized haemophilia centres resulted in a significantly increased life expectancy.

consequently in many plasma pools. 2 More refined products (eg, albumin) were, however, consistently TTV-negative. 2,3 These findings confirm longstanding experience, derived from numerous viral validation studies, of the Cohn HSA manufacturing process as one with a high capacity for removing viruses. The explanation for the recent unexpected findings 1 thus remains enigmatic. Using the same 2 TTV primer sets and a third independent in-house primer system, we confirmed earlier reports 2,3 from research groups at regulatory bodies who unanimously found HSA to be TTVnegative. Response:First-generation recombinant factor VIII concentrates are free from viral contaminations?Kreil et al (from Baxter BioScience) failed to detect TT virus (TTV) DNA in 11 lots of a Baxter first-generation recombinant factor VIII concentrate (rFVIII) (Recombinate) as well as in 13 lots of human serum albumin (HSA), a difference from our previously reported results. 1 As regards the rFVIII, the results of Kreil et al are not significantly different from ours (3 out of 13 were positive for TTV DNA). However, with regard to the contamination by TTV in HSA lots, the difference between the results obtained by the 2 groups is more evident. Kreil et al cite, as we too have done, the paper of Pisani et al, 2 who failed to detect TTV DNA in HSA, in order to strengthen their own conclusions. As we already stressed, Pisani et al used only the N22 polymerase chain reaction (PCR), which is unable to detect a high number of TTV variants. 3 In this case the difference in the methods used may well justify the different results. In addition, it is well known that, even using the same methods, the results obtained from different laboratories are not fully comparable if international standards are not available and used, as in the case of TTV so far. Furthermore, when the size of the study is so small, a negative result can be affected by a type II statistical error. According to the "rule of 3," the one-sided 95% confidence intervals of the Kreil et al study are 0 and 27.3. 4 Similar viral safety problems emerged concerning the possible contamination of several blood products by parvovirus B19. As regards the possibility of B19 contamination, we failed to detect B19 DNA in either rFVII or HSA, even using very sensitive nested PCR, whereas other groups reported different results. 5,6 It is likely that the residual amount of virus (or better, of viral genome) (TTV or B19 virus or perhaps other viruses) in such products after the manufacturing process is very low, near to the limit of sensitivity of the analytical methods available at present.Such a condition, in addition to the lack of standardization of methods, makes a comparison of results obtained in different laboratories very hazardous.We would like to emphasize again the need for continuous drug-surveillance with prospective protocols of informative hemophiliacs, treated for the first time even with rDNA-derived clotting factor concentrates. In addition, there is also the need to implement the stan...

Summary The factors associated with persistent instability of oral anticoagulant treatment (OAT) were investigated in a case‐control study. The most unstable patients from 35 Italian anticoagulation clinics were matched with stable controls, for gender, age and OAT indication. Socio‐demographic data, medical history, dietary and life habits, cytochrome P450 CYP2C9 variants, blood cell count, liver and renal functions were investigated. An ‘Abbreviated Mental Test’ (AMT) and a questionnaire to assess patient compliance to, and comprehension of, OAT indications and mechanisms were administered. An International Normalized Ratio (INR) above 4·5 was more frequently found in cases (n = 77) than controls (n = 80) (12·3% vs. 0·4%; P < 0·0001). The odds ratio for instability was significantly higher for: people who worked versus pensioners, acenocoumarol versus warfarin, and an insufficient score in the AMT and/or in the questionnaire. Cytochrome P450 CYP2C9 variants *1/*3 or *2/*3 or *3/*3 were more frequent among cases than controls (29·9% vs.15·0%; P = 0·042). No differences were observed as regards the other variables. In conclusion, we found that high intra‐individual variability in OAT control was multifactorial, but poor OAT comprehension was prevalent.

Summary. Background: Pretest clinical probability with the Wells rule and D-dimer have been widely investigated for the diagnosis of symptomatic proximal deep vein thrombosis (DVT) of the lower limbs, but they have not been formally tested for symptomatic isolated distal DVT diagnosis. Objective: To evaluate the diagnostic accuracy of the Wells rule and D-dimer for isolated distal DVT. Design, Setting, and Patients: This was a single-center, cross-sectional study including 873 consecutive outpatients with suspected DVT, in whom pretest clinical probability determination, D-dimer determination (STA Liatest; cut-off of < 500 ng mL) and complete compression ultrasonography of both lower limbs were performed. Results: The isolated distal DVT prevalence was 12.4% (90/725). The sensitivity of the Wells rule for isolated distal DVT was 47% (95% confidence interval [CI] 36-57%), the specificity was 74% (95% CI 70-77%), and the negative and positive predictive values were 91% (95% CI 88-93%) and 20% (95% CI 15-26%), respectively. Patients with isolated distal DVT had higher D-dimer levels than patients without DVT (1759 ± 1576 vs. 862 ± 1079 ng mL )1 , P = 0.0001). D-dimer was negative in 13 patients with isolated distal DVT. D-dimer sensitivity and specificity for isolated distal DVT were 84% (95% CI 75-91%) and 50% (95% CI 46-54%), respectively, with a negative predictive value of 96% (95% CI 93-98%). In patients with low pretest clinical probability, the D-dimer negative predictive value was 99% (95% CI 95-100%). Conclusion: In clinically suspected DVT with negative proximal compression ultrasonography, pretest clinical probability with the Wells rule has a low diagnostic accuracy for isolated distal DVT. D-dimer has a better negative predictive value, but alone it does not exclude isolated distal DVT. In patients with low pretest clinical probability, D-dimer had a negative predictive value of > 95% for isolated distal DVT.