Is there a multidisciplinary role for 5-methyltetrahydrofolate? The obstetric evidence in perspective.

5-methyltetrahydrofolate (5-MTHF), or its synthetic precursor, folic acid, is traditionally used as a supplement for improving fertility and for the prevention of embryonal neural tube defects. However, in the last decade, starting from the effectiveness of this preventive treatment in the gynecological setting, the use of 5-MTHF was extended to other medical and pathological areas. Thus, there might be a rationale for the use of 5-MTHF for purposes other than the protection of the growing embryo linked to the possible effect of MTHFR variants in different pathological conditions. A narrative review was conducted to provide an overview of the available evidence on the use of 5-MTHF in the obstetric field and to critically discuss the available data regarding the use of 5-MTHF across other different therapeutic areas. Results showed that the use of 5-MTHF in pregnancy presents some advantages if compared with folic acid, such as immediate action, the non-necessity of metabolic activation, and the immediate bioavailability of the mother and fetus. Otherwise, the role of 5-MTHF in the management of cardiovascular risk is still debated due to the multiple confounding factors that characterize this patient setting. A link between folate deficiency in pregnancy and postpartum depression has been proposed, as well as between folate levels and the onset of depression. In conclusion, evidence from the literature supports the additional role of 5-MTHF as a pleiotropic drug with a transversal effect in different therapeutic contexts. With regard to the prevention of cardiovascular disorders, available evidence is not conclusive.

Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow-up study.

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.

Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study.

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.

Prevalence of deep vein thrombosis and pulmonary embolism in patients with superficial vein thrombosis: a systematic review and meta-analysis.

UNLABELLED: 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.

Biosimilars of low-molecular-weight heparin products: fostering competition or reducing 'biodiversity'?

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.

A clinical score to rule out the concomitant presence of deep vein thrombosis in patients presenting with superficial vein thrombosis: The ICARO study.

BACKGROUND: 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. AIM OF THE STUDY: 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. METHODS: A multicenter, retrospective cohort study on SVT patients was conducted. Information was collected on clinical signs and on risk factors for venous thrombosis. RESULTS: 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). CONCLUSIONS: 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.

Pharmacological treatment and prevention of chronic venous ulcers: a review.

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.

Periprocedural management of antithrombotic therapy and open issues in cancer patients.

Perioperative management of patients who are receiving anticoagulant or antiplatelet drugs and require surgical or invasive procedure is a dilemma for clinicians. The discontinuation exposes the patient to an exceedingly high risk of thromboembolism while there is an exceedingly high bleeding risk if antithrombotic therapy is continued, strictly related to the type of surgery. This complex management is based on the assessment of thromboembolic and bleeding risk. In this review we analyze the strategies to optimize the perioperative use of antithrombotic drugs with special attention to new oral anticoagulant drugs, also in cancer patients.

New predictive approaches for ITI treatment.

Immune tolerance induction (ITI) therapy in patients with haemophilia A and inhibitors constitutes a huge burden for affected patients and families and poses a large economic burden for a chronic disease. Concerted research efforts are attempting to optimize the therapeutic approach to the prevention and eradication of inhibitors. The Italian ITI Registry has provided data on 110 patients who completed ITI therapy as at July 2013. Analysis of independent predictors of success showed that, together with previously recognized factors - namely inhibitor titre prior to ITI, historical peak titre and peak titre on ITI - the type of causative FVIII gene mutation also contributes to the identification of patients with good prognosis and may be useful to optimize candidate selection and treatment regimens. Numerous studies have demonstrated that inhibitor reactivity against different FVIII products varies and is lower against concentrates containing von Willebrand factor (VWF). An Italian study compared inhibitor titres against a panel of FVIII concentrates in vitro and correlated titres with the capacity to inhibit maximum thrombin generation as measured by the thrombin generation assay (TGA). Observations led to the design of the PredictTGA study which aims to correlate TGA results with epitope specificity, inhibitor reactivity against different FVIII concentrates and clinical data in inhibitor patients receiving FVIII in the context of ITI or as prophylactic/on demand treatment. At the immunological level, it is known that T cells drive inhibitor development and that B cells secrete FVIII-specific antibodies. As understanding increases about the immunological response in ITI, it is becoming apparent that modulation of T-cell- and B-cell-mediated responses offers a range of potential new and specific approaches to prevent and eliminate inhibitors as well as individualize ITI therapy.

Magnetic resonance imaging and ultrasound evaluation of "healthy" joints in young subjects with severe haemophilia A.

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.

Management of patients with long-term inhibitors: is immune tolerance an underestimated life-long solution?

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.

Management of bleeding disorders in adults.

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.

Molecular analysis and genotype-phenotype correlation in patients with antithrombin deficiency from Southern Italy.

We 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.

Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies.

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.

Coronary artery disease, cerebral non-fatal ischemic stroke in retinal vein occlusion: an 8-yr follow-up.

Forty-five consecutive subjects (26M, 19F; mean age 54 ± 14 yrs) with a diagnosed retinal vein occlusion (RVO), were followed-up for 8 yrs. As many as 145 sex-age- and blood pressure-matched individuals (78M, 67F; mean age 54.4 ± 13.5 yrs), that did not experience any vascular event, served as controls. At the time of the RVO, controls and subjects did not differ as to hypercholesterolemia, hypertrigliceridemia, diabetes mellitus, smoking habits, inherited/acquired thrombophilia. At the follow-up completion, they differed as to statin consumption (p = 0.016). During the 8-yrs follow-up, in the control population, 11 out of 145 (7.6%) subjects had experienced a major vascular event (8 coronary artery disease; 3 cerebral non-fatal ischemic stroke). In contrast, of the 45 subjects with a history of RVO, as many as 10 (22.2%) had experienced a major vascular event: 4 coronary artery disease; 4 cerebral non-fatal ischemic stroke; 2 cardiovascular + cerebrovascular event (p = 0.012). A prolonged antiplatelet treatment, prior to the major vascular event, was found in 5/45 cases (11.1%) vs 23/145 (15.9%) controls (p = 0.63). In contrast, a long-lasting administration of anti-hypertensive drugs, to achieve a control of blood pressure, was found in 83.4% of controls and only in 46.7% of cases (p < 0.0001). In conclusion, in a 8-yr follow-up, coronary artery disease and/or non-fatal ischemic stroke were more common in subjects with a history of RVO than in a large setting of subjects comparable for cardiovascular risk factors. These data also argue for RVO as a vascular disease in which aggressive anti-hypertensive therapy to prevent stroke and/or myocardial infarction is needed.

Diabetes mellitus and cardiovascular prevention: the role and the limitations of currently available antiplatelet drugs.

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.

Aspirin resistance and platelet turnover: a 25-year old issue.

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".