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Essentials Late sequelae of isolated superficial vein thrombosis (iSVT) have rarely been investigated. We studied 411 consecutive outpatients with acute iSVT with a median follow-up of three years. Male sex and cancer are risk factors for future deep vein thrombosis or pulmonary embolism. Patients without cancer appear to be at a negligible risk for death. SUMMARY Background Studies of long-term thromboembolic complications and death following acute isolated superficial vein thrombosis (iSVT) of the lower extremities are scarce. Objectives To investigate the course of iSVT in the setting of an observational multicenter study. Methods We collected longitudinal data of 411 consecutive outpatients with acute, symptomatic, objectively diagnosed iSVT who were previously included in the cross-sectional ICARO study. Four patients followed for < 30 days and 79 with concomitant deep vein thrombosis (DVT) or pulmonary embolism (PE) were excluded from the present analysis. The primary outcome was symptomatic DVT or PE. The safety outcomes were major bleeding and all-cause death. Results The median follow-up time was 1026 days (interquartile range 610-1796). Symptomatic DVT/PE occurred in 52 (12.9%) patients, giving annualized rates of 1.3% (95% confidence interval [CI] 0.3-3.9%) on anticoagulant treatment and 4.4% (95% CI 3.2-5.8%) off anticoagulant treatment. Male sex (adjusted hazard ratio [HR] 2.03 [95% CI 1.16-3.54]) and active solid cancer (adjusted HR 3.14 [95% CI 1.11-8.93]) were associated with future DVT/PE, whereas prior DVT/PE failed to show significance, most likely because of bias resulting from prolonged anticoagulant treatment. Three major bleeding events occurred on treatment, giving an annualized rate of 1.4% (95 CI 0.3-4.0%). Death was recorded in 16 patients (annualized rate: 1.1% [95% CI 0.6-1.7%]), and was attributable to cancer (n = 8), PE (n = 1), cardiovascular events (n = 3), or other causes (n = 4). Conclusions The long-term risk of DVT/PE after anticoagulant discontinuation for acute iSVT is clinically relevant, especially in males and in the presence of active cancer. The risk of death appears to be negligible in patients without cancer.

Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first 'Altogether to Beat Cushing's syndrome' workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

Summary Immune tolerance induction (ITI) is recognized as the first choice treatment in haemophilic patients with inhibitors, with the aim of restoring safe and effective standard factor VIII replacement and, particularly, prophylaxis in children. For the latter, literature data and clinical practice support the optimal cost utility ratio of ITI. Indeed, the high success rate, the low incidence of inhibitor recurrence after successful ITI and the possibility of preventing joint deterioration, enable one to predict a considerable long-term reduction of costs in the majority of treated patients. Therefore, in spite of high costs and open issues about optimal regimens, ITI is actually attempted in virtually all children with inhibitors. Few patients with long-standing inhibitors presently undergo ITI, particularly in the case of severe bleeding tendency. In this setting, uncertainties concerning management are amplified by the paucity of literature data and psychological reluctance by both patients and treaters due to the perceived poor prognosis and the demanding treatment (also in terms of costs). However, clinical data suggest that the role of age at ITI start and of time interval from inhibitor diagnosis, as predictors of ITI outcome, should be considered in a larger framework of proposed and more established prognostic factors. Moreover, optimising ITI management, particularly with respect to inhibitor titre at ITI start and avoidance of adverse events or interruption of treatment, may also contribute to improve outcomes. Although the economic constraints of the present era significantly affect resources for such a high-cost treatment, the individual cost-utility ratio (bleeding tendency and risk of fatal bleeding, arthropathy and need for orthopaedic surgery, comorbidities, quality of life) should be assessed carefully to determine whether ITI is a suitable option and thus not preclude adults from the opportunity of inhibitor eradication.

Development of FVIII inhibitors is currently the most severe and challenging complication of haemophilia A treatment and represents a very large economic burden for a chronic disease. As a result, clinical research is making major efforts to optimize the therapeutic approaches for this condition. In this section we will review some important aspects of the management of haemophilia in adults, including an overview of bleeding in women with von Willebrand disease, an analysis of FVIII consumption in patients with severe haemophilia A, an update of the ongoing RES.I.ST study, long-term prophylaxis and experience from the Pro.Will study, current evidence relating to economic aspects of the treatment of haemophilic patients with inhibitors (based on the PROFIT study), and an overview of musculoskeletal complications in adults with severe bleeding disorders.

Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990-2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma-derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 10(3) patients (3.6 per 10(4) for severe AEs) and 1.13 per 10(5) infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment.

Background: Although patients with idiopathic VTE are at higher than normal risk of asymptomatic atherosclerosis and of cardiovascular events, the impact of cardiovascular risk factors on VTE is poorly understood. Objective: To assess the prevalence of the metabolic syndrome and of its components in patients with early-onset idiopathic VTE. Methods: As many as 323 patients referred to our Thrombosis Ward for a recent (< 6-months) early-onset idiopathic venous thromboembolism (VTE), were compared with 868 gender- and age-matched subjects, in whom a history of venous thrombosis had been excluded, referred during the same period time to our Ward. All had undergone a clinical assessment for smoking habits and for the presence of the components of the metabolic syndrome. Results: The metabolic syndrome was detected in 76/323 cases (23.5%) and in 81/868 controls (9.3%) (p < 0.001; OR:2.990; 95%C.I.:2.119-4.217). Smoking was more common in patients with idiopathic VTE than in controls. In addition to the metabolic syndrome as a whole, its major individual determinants (arterial hypertension, impaired fasting glucose plasma levels, abdominal obesity, hypertriglyceridemia, low HDL-cholesterol) significantly correlated with idiopathic VTE (p always < 0.05). The prevalence of thrombotic events was lower in females than in males (p = 0.000; OR:2.217), the latter being most often hypertensives, smokers, hypertriglyceridemics, carriers of a metabolic syndrome and of impaired fasting glucose than females. In a multivariate analysis, arterial hypertension, impaired fasting glucose, abdominal obesity, and hypercholesterolemia independently predicted idiopathic venous events. Conclusions: Both metabolic syndrome as a whole and its major components individually considered, independently predict early-onset idiopathic VTE.

Inhibitor development, because of its impact on patients' morbidity and quality of life, is presently the most serious complication of haemophilia A treatment. The identification of several genetic and non-genetic risk factors may be used for the stratification of inhibitor risk and the definition of prevention strategies, particularly for patients with a high-risk genetic profile. The most extensively studied genetic factor is the type of F8 mutation, i.e. large deletions, nonsense mutations and inversions, which are associated with a higher risk of inhibitor development. This is the basis for the increased risk in patients with inhibitor family history; however, concordance family studies showed that factors other than F8 mutations are involved. An emerging role is investigated for polymorphisms of immune-regulatory genes that may increase (IL-10 and TNF-alpha) or reduce (CTLA-4) inhibitor risk and whose heterogeneous ethnic distribution may correlate to the higher inhibitor risk in non-caucasian patients. A role for FVIII haplotypes, particularly in black haemophiliacs, has been recently proposed. Recent studies report an increased inhibitor risk for initial intensive treatments (surgery or severe bleeds requiring high-dose and/or prolonged treatment, presence of danger signals), whereas regular prophylaxis (absence of danger signals) exerts a protective effect. A clinical score including the type of F8 mutation, family history of inhibitors and intensive treatment has been recently validated for predicting inhibitor risk. Because of the lack of useful data regarding the role of different types of FVIII concentrates, the stratification of risk in patients starting replacement treatment together with the careful evaluation of indications, doses and duration of treatment at first exposures and further efforts for overcoming barriers to early implementation of prophylaxis are encouraged, particularly for patients with a predictable high inhibitor risk.

SummaryIn the 1980s, observational retrospective studies showed an inverse relation between coronary heart disease (CHD) and consumption of fish containing fatty acids that belong to the omega (ω)-3 family. Large case-control studies and prospective intervention trials consistently showed that ω-3 fatty acids supplementation lowers fatal myocardial infarction (MI) and sudden cardiac death. By analysing the strengths of the results of individual studies and how the meta-analyses agree with them, putting together relevant backgrounds, and identifying open questions, the following findings/directions emerge. (i) Dietary and non-dietary intake of ω-3 fatty acids reduces overall mortality, mortality due to MI, and sudden death in patients with CHD; (ii) Fish oil consumption directly or indirectly affects cardiac electrophysiology. Fish oil reduces heart rate, a major risk factor for sudden death; (iii) Among patients with implantable cardioverter defibrillators, ω-3 fatty acids do not reduce the risk of ventricular tachycardia/ventricular fibrillation and may actually be pro-arrhythmic; (iv) The consumption of ω-3 fatty acids leads to a 10–33% net decrease of triglyceride levels. The effect is dose-dependent, larger in studies with higher mean baseline triglyceride levels, and consistent in different populations (healthy people, people with dyslipidaemia, diabetes, or known cardiovascular risk factors); (v) Outcomes for which a small beneficial effect ω-3 fatty acids is found include blood pressure (about 2 mmHg reduction), re-stenosis rates after coronary angioplasty (14% reduction), and exercise tolerance testing. Major experimental data provide strength (biological plausibility) for these findings, and define directions for newer clinical trials with ω-3 fatty acids.

Introduction: Eighty-six adult patients with GH deficiency (GHD) of adult or childhood onset were treated for 6 months, with recombinant human growth hormone (r-hGH) at a low (LD) or conventional dose (CD). The treatment effect on insulin levels was investigated. Methods: This manuscript refers to the Italian addendum to an International Study (B9R-EW-GDED) in which patients with GHD were randomized to receive r-hGH replacement therapy at a dose of either 3 μg/kg/day or 6 μg/kg/day for the 3 months. The dose was then doubled for the next 3 months. Results: After 6 months of r-hGH treatment, insulin levels increased with both GH dosages, with a greater increase achieved in the low-dose subgroup. Insulin levels also increased significantly in the childhood-onset, while even decreased in the adult-onset subgroup. On the whole, in more than 50% of patients, insulin values rose by >13%. Moreover, mean levels of IGF-I increased 2–3 fold (p

Haemophilia A (HA) is an X-linked recessive haemorrhagic disorder caused by a deficiency of coagulation factor VIII. Disease causative mutations are heterogeneous and spread all over the F8 gene sequence, with the exception of intron 22 inversion occurring in about 50% of severe patients. To define the specific mutational repertoire and mutation detection rate, we analysed F8 gene, by polymerase chain reaction and direct sequencing, in 128 unrelated patients from Southern Italy with severe (n = 108), moderate (n = 9) or mild (n = 11) HA. We identified 120 mutations, including 64 cases of intron 22 inversion (53.3%), three of intron 1 inversion (2.5%), one large deletion (0,8%) and 52 point mutations (43.3%). In particular, 19/120 were novel and 7/52 point mutations (13.5%) occurred at CpG sites. We also investigated eight prothrombotic genetic variants in a subgroup of 74 severe HA patients to evaluate their possible protective effect on the severity of clinical expression. Methylenetetrahydrofolate reductase A1298C and plasminogen activator inhibitor-1 4G variants recurred more frequently in HA patients with a less-severe phenotype. Clinical impact of these findings needs large-scale studies to further define the role of these prothrombotic variants as possible modifier factors of HA phenotype.

The term 'biosimilars' is used to qualify products developed to be similar to an original biological drug. Biosimilars are much more complicated to develop than a generic version of small-molecule drugs and this is especially true for low-molecular-weight heparins (LMWHs). Evidence on the antithrombotic management of acute coronary syndromes (ACS) showed that the introduction into the market of biosimilars approved on the basis of simple biological criteria, without robust data from comparative clinical trials, may be hazardous. Moreover, the mixtures of LMWH polysaccharide chains, some immunoallergic properties and potential contamination during the extraction process raise safety concerns. As was the case for the biosimilar erythropoietin, there is the risk that only copies of the most commercially successful LMWHs will be marketed, thus jeopardizing the 'biodiversity' now ensured by the presence of several LMWHs, each with unique features that support the use of an individual LMWH as first-choice therapy in certain categories of patients.

Introduction Pharmacokinetic (PK) studies on recombinant FIX concentrate, Nonacog alpha, were conducted with different sampling time designs which gave rise to not complete and homogenous outcomes. In addition, patient's FIX genotype/PK relationship has never been investigated. Aim Investigate how different sampling times may affect PK parameters and try to find a FIX genotype/PK relationship. Patients and Methods A cohort pharmacokinetic, Nonacog Alpha single-dose, open-label, non-comparative study was conducted in eight Comprehensive Care Haemophilia Centres in Italy. Seventeen previously treated moderate or severe haemophilia B patients were enrolled. Factors IX:C one-stage clotting assay, FIX genotype and PK analysis were centralized. Results The evaluation of PK outcomes showed a quite long half-life, smaller clearance and volume of distribution of Nonacog Alpha in comparison with the results from previously reported studies, where blood sampling was stopped too early. The relationship between PK outcomes and FIX genotype showed that small deletions displayed the higher clearance and shorter half-life, the nonsense mutations (the lower and the longer respectively), and missense mutations were in between. Conclusions It is evident that area under the curve (AUC) and other PK parameters depend from the sampling time design. In order to have a complete evaluation of clotting factors in vivo decay, blood samples must be collected until the baseline factor concentration has been achieved again. Due to the relationship between FIX genotype and clearance, tailored prophylaxis of HB patients could be partially predicted by genotyping.

Summary. Following the first clinical use in haemophilia and von Willebrand disease in 1977, the synthetic analogue of vasopressin 1-deamino-8-d-arginine vasopressin (DDAVP, desmopressin) was successfully employed for the management of a series of bleeding disorders, including congenital and acquired defects of platelet function. In this setting, few haemostatic approaches are available and, in particular for severe bleeding and major invasive procedures, the transfusion of platelet concentrates is the first-choice treatment. Therefore, DDAVP was (and remains) an attractive therapeutic alternative, being well tolerated, cost-saving, administrable at home (by the intranasal or subcutaneous concentrated formulations) and, in particular, enabling the avoidance of blood product exposition and the related risks (allergic reactions, transfusion transmitted infections). Despite three decades of clinical use, cellular mechanisms of haemostatic effects of DDAVP in platelet defects remain poorly known and the excellent results reported in some case series have not been strengthened by rigorous clinical trials, hampered by the rarity and the heterogeneity of these disorders. However, clinical experience more than evidence-based medicine reserved an established place to DDAVP in the management of inherited platelet disorders. This review will focus the available clinical data and the open issues of DDAVP in this setting.

Essentials The association of superficial vein thrombosis (SVT) with venous thromboembolism (VTE) is variable. We performed a meta-analysis to assess the prevalence of concomitant VTE in patients with SVT. Deep vein thrombosis was found in 18.1%, and pulmonary embolism in 6.9%, of SVT patients. Screening for VTE may be worthy in some SVT patients to plan adequate anticoagulant treatment. Summary Background Some studies have suggested that patients with superficial vein thrombosis (SVT) have a non-negligible risk of concomitant deep vein thrombosis (DVT) or pulmonary embolism (PE) at the time of SVT diagnosis. Unfortunately, the available data on this association are widely variable. Objectives To perform a systematic review and meta-analysis of the literature in order to evaluate the prevalence of concomitant DVT/PE in patients with SVT of the lower limbs. Methods Studies reporting on the presence of DVT/PE in SVT patients were systematically searched for in the PubMed, Web of Science, Scopus and EMBASE databases. The weighted mean prevalence (WMP) of DVT and PE was calculated by use of the random effect model. Results Twenty-one studies (4358 patients) evaluated the prevalence of DVT and 11 studies (2484 patients) evaluated the prevalence of PE in patients with SVT. The WMP of DVT at SVT diagnosis was 18.1% (95%CI: 13.9%, 23.3%) and the WMP of PE was 6.9% (95%CI: 3.9%, 11.8%). Heterogeneity among the studies was substantial. Selection of studies including outpatients only gave similar results (WMP of DVT, 18.2%, 95% CI 12.2–26.3%; and WMP of PE, 8.2%, 95% CI 3.3–18.9%). Younger age, female gender, recent trauma and pregnancy were inversely associated with the presence of DVT/PE in SVT patients. Conclusions The results of our large meta-analysis suggest that the prevalence of DVT and PE in patients presenting with SVT is not negligible. Screening for a major thromboembolic event may be worthwhile in some SVT patients, in order to allow adequate anticoagulant treatment to be planned. Other high-quality studies are warranted to confirm our findings.

Chronic venous insufficiency and chronic venous ulcers represent an important medical problem, because of the high incidence and prevalence in the general population, and need to be considered as a lifelong degenerative condition, with socioeconomic consequences. Ulceration is a severe complication of the post-thrombotic syndrome, often precipitated by minor trauma. The rate of post-thrombotic syndrome varies between 20% and 100% of patients with deep vein thrombosis, mostly occurring within two years of an initial thrombotic event. This syndrome is difficult to treat, causes significant disability and reduces the quality of life. To date, there are no effective therapies of chronic venous ulcers and no definite strategies for identifying patients at risk for the development of ulceration. The role of adequate compression with elastic stockings is well recognized. Several systemic drugs have been tested for a possible effect on chronic venous ulcer healing, but none has been widely accepted as standard therapy in this setting. It has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure. Waiting for the results in this field, an adequate management of anticoagulation in terms of anticoagulant intensity and duration should be recommended for the prevention of recurrent deep vein thrombosis, post-thrombotic syndrome and chronic venous ulcers.

Superficial vein thrombosis (SVT) is commonly encountered in clinical practice. Recent studies have suggested that the concomitant presence of deep vein thrombosis (DVT) or pulmonary embolism (PE) at the time of SVT diagnosis is not uncommon, thus increasing the interest on this disease. Whether this coexistence is predicted by specific risk factors remains unknown.To evaluate potential risk factors for DVT coexistence in patients presenting with acute objectively diagnosed SVT of the lower limbs and to develop a simple score entirely based on clinical variables to define the pre-test probability of DVT in these patients.A multicenter, retrospective cohort study on SVT patients was conducted. Information was collected on clinical signs and on risk factors for venous thrombosis.494 patients (mean age 56.3 ± 17.9 years, 64.2% women) were included. Concomitant DVT was found in 16.0% of patients. After multivariate analysis, we identified 5 independent variables that were used to develop the ICARO score: active malignancy (1.5 points), limb edema (1.5 points), rope-like sign (-1 point), age ≥ 50 years (1 point), unprovoked SVT (-1 point). The prevalence of concomitant DVT was 1.1% in the low-probability category (0 points), 12.0% in the intermediate-probability category (0 to 1 points), and 32.3% in the high probability category (≥ 1.5 points).The concomitant presence of major DVT is not negligible in patients with SVT. Our prediction score entirely based on simple clinical variables may be useful in assessing the risk of concomitant DVT in these patients.

Coppola A, De Stefano V, Tufano A, Nardone G, Amoriello A, Cerbone AM, Di Minno G (Centro di Coordinamento Regionale per le Emocoagulopatie; Universita‘Federico II’, Napoli; A.O.R.N. ‘A. Cardarelli’, Napoli; Italy). Long-lasting intestinal bleeding in an old patient with multiple mucosal vascular abnormalities and Glanzmann's thrombasthenia 3-year pharmacological management (Case report). J Intern Med 2002; 252: 271–275. A 75-year-old woman with Glanzmann's thrombasthenia was admitted because of persistent melaena. Endoscopic examination showed multiple angiodysplastic lesions, with active bleeding in small and large bowel. Electro-coagulation of some lesions, octreotide, conjugated oestrogens and selective embolization of jejunal vessels did not change transfusion requirements. After 8 month-transfusions, ethinylestradiol + norethisterone in association with octreotide was started, leading to no transfusion over the following 9 months. Bleeding recurred after withdrawing octreotide and substituting ethinylestradiol + norgestrel for the ethinylestradiol + norethisterone combination. Re-introduction of octreotide did not improve bleeding; however, a reduction of transfusion requirement was observed when the ethinylestradiol + norethisterone pill was re-administered. The association of octreotide and of an oestrogen–progesterone combination was helpful in the difficult management of recurrent bleeding in this patient with diffuse gastrointestinal vascular abnormalities and a severe condition predisposing to bleeding.

Acute coronary syndrome and severe haemophilia: An unusual association with challenging treatment

Background Genetic factors are involved in the development of diabetic nephropathy in Type 1 diabetes. We have examined the association of four candidate genes, angiotensin converting enzyme (ACE): insertion/deletion (I/D) polymorphism, plasminogen activator inhibitor-1 (PAI-1): 4G/5G polymorphism, decorin: 179/183/185 polymorphism and Werner syndrome helicase: C/R polymorphism, with the presence of diabetic nephropathy in Type 1 diabetic patients. Methods 175 Type 1 diabetic patients with albuminuria (59 with microalbuminuria and 116 with macroalbuminuria) were compared with 136 Type 1 diabetic patients with normoalbuminuria and duration of disease longer than 15 years (meantSD: 25t8 years). 200 non-diabetic subjects were also studied as background population. Results We found no association in the polymorphism of the four genes examined between patients with and without diabetic nephropathy and the control subjects. Conclusions The genes studied are unlikely to be involved in the susceptibility to nephropathy in Type 1 diabetic patients. Copyright # 1999 John Wiley & Sons, Ltd.

Background The angiotensin-converting enzyme gene insertion (I)/deletion (D) polymorphism might be involved in the development of several cardiovascular diseases, but its role in humans remains controversial. Objective To investigate the relation between the angiotensin converting enzyme gene polymorphism and extent of blood pressure elevation in arterial hypertension, taking into account the influence of cardiovascular risk factors. Methods We studied 171 patients (aged 49 ± 9 years, 61 women) with abnormal clinic and 24 h ambulatory blood pressures, after a 3-week wash-out. Results We found no significant difference in clinic and ambulatory blood pressures among homozygotic D (DD), heterozygotic D (ID) and homozygotic l (II) angiotensin converting enzyme genotypes and between homozygotic D (DD) and pooled heterozygotic D (ID) plus homozygotic l (II) (non-DD) angiotensin converting enzyme genotypes. At least one additional cardiovascular risk factor (smoking, hypercholesterolaemia or diabetes) was present for 103 patients (33 DD and 70 non-DD). Non-DD subjects (n = 43) without additional cardiovascular risk factors exhibited lower values of 24 h, daytime systolic and pulse blood pressures than did members of all other groups (all P< 0.04). In the presence of risk factors, DD and non-DD subjects exhibited similar systolic and pulse ambulatory blood pressures, in that we found higher values in non-DD genotype subjects with risk factors than we did for non-DD subjects without additional risk factors. In multivariate analysis, the combination of non-DD genotype and absence of cardiovascular risk factors was associated with the lowest values of systolic and pulse blood pressures. Conclusions Angiotensin converting enzyme insertion allele appears clustered with lower ambulatory systolic and pulse blood pressures in hypertensive patients when the potential interference of additional cardiovascular risk factors is eliminated. A high prevalence of cardiovascular risk factors in population studies might blunt a possible biological association of blood pressure with DD genotype by contributing to raising of blood pressures also in subjects with non-DD genotypes.

Intron 1 and intron 22 inversions (inv1 and inv22) represent the most prevalent mutations in the F8 gene (F8) (1-5% and 40-45%, respectively) causative of severe haemophilia A (HA) [1]. These alterations result from intrachromosomal recombination between intronic regions (int1h-1 and int22h-1, respectively) and their homologous extragenic copies in telomeric position (int1h-2 and int22h-2/3, respectively) [1]. Inv1 causes an altered F8 structure with the translocation and inversion of the 5' region including exon 1 in the extragenic site, giving rise to 2 chimeric mRNAs: one containing the promoter and first exon of the F8 followed by some exons of the VBP1 gene; the other one formed by the promoter and coding sequences of the C6.1A gene joined to a part of the intron 1 and exons 2-26 of the F8 [2]. © 2012 International Society on Thrombosis and Haemostasis.

Magnetic resonance imaging (MRI) and ultrasonography (US) are increasingly used in haemophilia A (HA) to detect early joint changes. A total of 40 clinically asymptomatic joints, never involved by bleeding events ["healthy joints" (HJ)], were evaluated by MRI and, in parallel, by US in 20 young subjects with severe HA (22.45 ± 2.72 years old; no history of arthritides, of viral infections or of inhibitors against factor VIII). The same joints were evaluated in 20 matched non-haemophilic (no-HA) subjects (mean age 23.90 ± 2.31 years, P = 0.078 vs. HA subjects). US images were obtained with specific probe positions according to validated procedures. A validated US score and progressive (P-MRI) and additive (A-MRI) MRI scores were employed for data collection and analysis. The US score was higher in HA than in no-HA subjects (3.40 ± 1.72 vs. 0.80 ± 1.10, P < 0.001). Taking into account only moderate/severe alterations, joint effusion was found in 55% of HA and in 5% of no-HA joints (P < 0.001); synovial hypertrophy was found in 20% of HA and in none of the no-HA joints; cartilage erosion was found in 30% of HA and in none of no-HA joints. MRI examinations confirmed these findings and the US score correlated with the A-MRI (r = 0.732, P < 0.001) and with the P-MRI (r = 0.598, P < 0.001) scores. MRI and US data significantly correlated as to effusion (r = 0.819, P = 0.002), synovial hypertrophy (r = 0.633, P = 0.036) and cartilage erosion (r = 0.734, P = 0.010). Despite inherent limitations, joint US examination identified subclinical abnormalities of HJ in young subjects with severe HA.

The role of the metabolic syndrome in patients with provoked venous thromboembolic events

Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990-2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma-derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 10(3) patients (3.6 per 10(4) for severe AEs) and 1.13 per 10(5) infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment.

Development of FVIII inhibitors is currently the most severe and challenging complication of haemophilia A treatment and represents a very large economic burden for a chronic disease. As a result, clinical research is making major efforts to optimize the therapeutic approaches for this condition. In this section we will review some important aspects of the management of haemophilia in adults, including an overview of bleeding in women with von Willebrand disease, an analysis of FVIII consumption in patients with severe haemophilia A, an update of the ongoing RES.I.ST study, long-term prophylaxis and experience from the Pro.Will study, current evidence relating to economic aspects of the treatment of haemophilic patients with inhibitors (based on the PROFIT study), and an overview of musculoskeletal complications in adults with severe bleeding disorders.

SummaryWe sequenced the SERPINC1 gene in 26 patients (11 males) with antithrombin (AT) deficiency (22 type I, 4 type II), belonging to 18 unrelated families from Southern Italy. Heterozygous mutations were identified in 15/18 (83.3%) families. Of them, eight were novel mutations, each being identified in one family. Seven clearly cause impaired protein synthesis (four frameshift, one non-stop, one splicing and one 21bp deletion). One, present in a single patient, is a missense mutation thought to be causative because: a) it is absent in 100 chromosomes from controls; b) it involves a highly conserved amino acid, whose change is predicted to impair AT activity; c) no other mutation is present in the propositus. Severe mutations (i.e. nonsense, frameshift, deletions) were invariably identified in type I patients. In type II patients, 3/4 were missense mutations; the fourth leads to a 19 nucleotides shift in the stop codon. In addition to the type of mutation, the co-existence of other predisposing factors in most patients helps explain the severity of the present type I cases (age at first event, recurrence during prophylaxis). In the five families in which there was more than one member affected, the same genotype and a concordant clinical expression of the disease were found. We conclude that the molecular bases of AT deficiency in Southern Italy are different as compared to other geographic areas, and that molecular analysis and the study of the effect of the mutation may help predict the clinical expression of the disease.

Background Mesenteric vein thrombosis (MVT) is a rare, often lethal, entity that accounts for approximately 10-15% of all cases of mesenteric ischemia [1,2]. Current indications for surgery in patients with acute MVT include signs of peritonitis, bowel infarction and hemodynamic instability. In all other cases, long-lasting anticoagulation is the strategy of choice [3,4], patients with MVT have a fairly good prognosis and long-term outcomes once appropriate anticoagulation is achieved [4,5]. At variance with the slow onset of recanalization that takes place during anticoagulation, thrombolysis leads to a rapid re-opening of a vessel, with immediate tissue reperfusion [4].

The evidence of an incomplete inhibition of platelet function by aspirin, despite therapeutic doses of the drug proved to be clinically effective are employed, was first reported in the '80s, in the frame of studies devoted to platelet turnover. Because inhibition of platelet aggregation by aspirin is irreversible, the return after an interval of time of the ability to form thromboxane by platelets in circulating blood should reflect the entry into the circulation of platelets whose cyclooxygenase activity has not been affected by aspirin. Based on this concept, the possibility of monitoring the entry of newly formed platelets into the circulation after aspirin ingestion was documented by measuring the return of thromboxane biosynthesis by platelets challenged in vitro by pairs of aggregating agents. The data obtained showed that platelets with intact cyclooxygenase activity could be detected into the circulation of control individuals as early as 4-6 h after aspirin ingestion, and at shorter time intervals in diabetic angiopathy. In the latter setting, the data allowed to conclude that "schedules of aspirin which may suffice in normals are not effective in patients with diabetic angiopathy, presumably because these patients have a high rate of entry of new platelets into the circulation"

Diabetes mellitus (DM) is associated with macrovascular and microvascular complications. Platelets have a “key role” in atherogenesis and its thrombotic complications in subjects with DM. Moreover, the concomitant presence of multiple “classical” cardiovascular risk factors in diabetic subjects contributes to enhanced atherothrombotic risk. Antiplatelet agents are effective in primary and secondary prevention of arterial thrombosis (cardiovascular events, ischaemic stroke, and peripheral arterial occlusive disease). The role of chronic administration of antiplatelet drugs in primary prevention of arterial vascular events is known to be less clear than in secondary prevention, and, also in diabetic patients, the decision to give primary prophylaxis should be taken on an individual-patient basis, after a careful evaluation of the balance between the expected benefits and the risk of major bleedings. Although, currently, treatment has proven useful in reducing vascular events, diabetic patients continue to have a higher risk of adverse cardiovascular events compared with those in nondiabetic patients. This paper reviews the role of currently available antiplatelet drugs in primary and secondary prevention of vascular events in diabetic patients and the limitations of these drugs, and it discusses the role of novel and more potent antiplatelets and of new agents currently under clinical development.

Injected factor VIII (FVIII), the current treatment for haemophilia A, leads to major improvements in the quality of life and life expectancy of individuals with this disorder. However, because injected FVIII has a short half-life in vivo, this strategy has major limitations for highly demanding regimens (e.g. prophylaxis, immune tolerance induction, surgery). Newer formulations of longer-acting FVIII are presently under investigation. The use of low molecular weight polyethylene glycol (PEG)-containing liposomes as carriers for recombinant FVIII (rFVIII) results in the prolongation of haemostatic efficacy. Data from preclinical experiments in mice, early clinical evaluations, and pharmacokinetics and pharmacodynamics results indicate that an rFVIII pegylated liposomal formulation may provide potential clinical benefit to patients with severe haemophilia A by prolonging the protection from bleeding. In light of this potential clinical benefit, a multicentre, randomized, active-controlled, non-inferiority phase II trial with two parallel treatment arms and equal randomization after stratification for the presence or absence of target joints in patients and for ages >/=18 years vs.

In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of health-related quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.

Diabetes mellitus is commonly associated with both microvascular and macrovascular complications (coronary artery disease, cerebrovascular events, severe peripheral vascular disease, nephropathy and retinopathy). There is wide evidence demonstrating that platelet degranulation and synthesis of TxA2 are increased in diabetic patients. For this reason, many studies on anti-platelet therapy have been made to reduce thrombotic complication of diabetes mellitus. Some diabetic patients, although treated with ASA, have a high prevalence of recurrent thrombotic events, which may presumably be due to an "ASA resistance". Nevertheless, this drug remains the one with the greatest benefit. To optimize its function, we should try to understand the causes of "aspirin resistance", try to find the most suitable dosage, recommending patients to comply constantly with the prescription given and to avoid interactions with other drugs. "Clopidogrel resistance" is a term not clearly defined. The clinical implications of "clopidogrel resistance" are unknown. An important consideration affecting the use of aspirin in diabetic patients is its interaction with ACE-inhibitors. Another question is antiplatelet therapy in nephropathic diabetic patients. Although these patients are at high thrombotic and haemorrhagic risk, they should nevertheless be considered eligible to undergo antithrombotic therapy, taking into account the individual's haemorrhagic risk.

Congenital coagulation disorders limit the use of liver biopsy, especially when repeated assessment is needed. TGF-beta 1 plays a pivotal role in inducing fibrosis and has been proposed as its surrogate marker. Aiming at validating the clinical utility of this cytokine, fifteen haemophilic patients suffering from HCV-related chronic hepatitis were treated with Peg-IFN alpha2β plus Ribavirin. Serum TGF-beta 1, viral load and liver enzymes were analyzed at baseline and at six, twelve, and eighteen months. As expected, patients initially showed significantly higher TGF-beta 1 levels than age-matched controls (43.8 ng/mL, 28.7–46.4 vs. 26.9 ng/mL, 23.0–34.0, median and 95% CI; p=0.004). The end of therapy response rate was 67%. The main finding was a significant drop in TGF-beta 1 at six months compared to baseline values; this drop de facto predicted the levels reached in the following six months, which were fixed at lower concentrations (37.0 ng/mL, 21.9–43.8 and 27.0 ng/mL, 24.1–44.0 respectively; p

Epidemiological observations indicate that high plasma fibrinogen levels are strongly correlated with the frequency of two major thrombotic complications of atherosclerosis, stroke and myocardial infarction. Thrombosis is increasingly recognized as a central mechanism in stroke and myocardial infarction, and fibrinogen is involved in events thought to play a major role in thrombosis. Therefore, elucidation of the relationship between fibrinogen and thrombosis may strengthen the predictive value of this protein and suggest new treatment to prevent stroke and myocardial infarction. The current data relating fibrinogen to thrombosis are not easy to reconcile with the available epidemiological observations. In addition, advances in understanding the atherogenic potential of several risk factors for coronary heart disease have used information on the measurement of the risk factors in population-based studies. Thus, measuring plasma fibrinogen to predict stroke and myocardial infarction may be important in gaining insight into the thrombogenic potential of this protein and in inspiring new strategies against the thrombotic complications of atherosclerosis.

Objective— The purpose of this study was to investigate the effects of plasminogen activator inhibitor-1 (PAI-1) gene (SERPINE1) single nucleotide polymorphisms (SNPs) on the risk of myocardial infarction (MI), on PAI-1 levels, and factors related to the metabolic syndrome. Methods and Results— Eleven SNPs capturing the common genetic variation of the SERPINE1 gene were genotyped in the HIFMECH study. In the 510 male cases and their 543 age-matched controls, a significant gene-smoking interaction was observed. In nonsmokers, the rs7242-G allele was more frequent in cases than in controls (0.486 versus 0.382, P =0.013) whereas the haplotype derived from the rs2227631 (−844A>G)-G and rs2227683-A alleles was ≈3-fold lower in cases than in controls (0.042 versus 0.115, P =0.006). SERPINE1 haplotypes explained 3.5% ( P =0.007) of the variability of PAI-1 levels, which was attributable to the combined effects of 3 SNPs, −844A>G, rs2227666, and rs2227694. The rs6092 (Ala15Thr) and rs7242 SNPs acted additively to explain 4.4% of the variability of plasma insulin levels and 1.6% of the variability of BMI ( P −3 and P =0.023, respectively). Conclusions— SERPINE1 haplotypes are mildly associated with plasma levels of PAI-1 and with the risk of MI in nonsmokers. They are also associated with insulin levels and BMI.