Rate of post-bariatric hypoglycemia using continuous glucose monitoring: A meta-analysis of literature studies.

AIMS: Hypoglycemia is a serious complication of bariatric surgery. The aim of the present meta-analysis was to evaluate the rate and the timing of post-bariatric hypoglycemia (PBH) with different bariatric procedures using reliable data from continuous glucose monitoring (CGM). DATA SYNTHESIS: Studies were systematically searched in the Web of Science, Scopus and PubMed databases according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The prevalence of PBH was expressed as weighted mean prevalence (WMP) with pertinent 95% confidence intervals (95%CI). A total of 8 studies (16 datasets) enrolling 280 bariatric subjects were identified. The total WMP of PBH was 54.3% (95%CI: 44.5%-63.8%) while the WMP of nocturnal PBH was 16.4% (95%CI: 7.0%-34%). We found a comparable rate of PBH after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) (OR 1.62, 95%CI: 0.71-3.7; P = 0.248); likewise, the percent time spent in hypoglycemia was similar with the two procedures (mean difference 5.3%, 95%CI: -1.4%-12.0%; P = 0.122); however, RYGB was characterized by a higher glycemic variability than SG. Regression models showed that the time elapsed from surgical intervention was positively associated with a higher rate of both total PBH (Z-value: 3.32, P < 0.001) and nocturnal PBH (Z-value: 2.15, P = 0.013). CONCLUSIONS: PBH, both post-prandial and nocturnal, is more prevalent than currently believed. The rate of PBH increases at increasing time from surgery and is comparable after RYGB and SG with a higher glucose variability after RYGB.

Promoting physical activity in people with haemophilia: the MEMO (Movement for persons with haEMOphilia) expert consensus project.

Regular physical activity can increase joint stability and function, reduce the risk of injury, and improve quality of life of people with haemophilia (PwH). However, a recent review of the literature shows that appropriate physical activity and sport are not always promoted enough in the overall management of PwH. A group of Italian experts in haemophilia care undertook a consensus procedure to provide practical guidance on when and how to recommend physical exercise programmes to PwH in clinical practice. Three main topics were identified -haemophilia and its impact on movement, physical activity recommendations for PwH, and choice and management of sports activity in PwH- and ten statements were formulated. A modified Delphi approach was used to reach a consensus. The group also created practical tools proposing different physical activities and frequencies for different age groups, the Movement Pyramids, to be shared and discussed with patients and caregivers. In conclusion, in the opinion of the working group, physical activity can be considered as a low-price intervention that can prevent/reduce the occurrence of chronic diseases and should be further encouraged in PwH to obtain multiple physical and psychological benefits. Future research should include prospective studies focusing on participation in sports, specific risk exposure and clinical outcomes.

Pain assessment and management in Italian Haemophilia Centres.

BACKGROUND: Although the widespread use of factor VIII/IX replacement therapy has significantly reduced the severity of arthropathy in persons with haemophilia (PWH), some develop degenerative joint changes, associated with significant pain. The aim of this survey was to investigate the management and perception of pain among Italian physicians who treat PWH. MATERIALS AND METHODS: Between September and October 2017, a questionnaire was distributed to 35 Italian haemophilia treatment centres (60 physicians). RESULTS: Fifty-three haemophilia specialists completed the survey. We found that there was good agreement (98.1%) on the need to investigate pain at each clinical visit, but there was heterogeneity in the opinions of haemophilia specialists with regards to the availability of validated guidelines (35.8%) and whether pain specialists should be a part of the comprehensive care team in daily clinical practice (58.5%). Haemophilia specialists also agreed pain should be evaluated using a rating scale validated in PWH (88.7%). Pain was mainly managed by the haemophilia specialists themselves, supported by a physiatrist and physiotherapist, while a pain specialist was only involved in 26.4% of cases. The combination of paracetamol with tramadol or codeine was the most common first-line treatment, while cyclo-oxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs, and opioids were less commonly used. DISCUSSION: There are some unmet needs in Italy regarding pain management for PWH and the management of pain in these patients by haemophilia specialists. There is a lack of evidence-based guidelines for these specialists to use, as well as a reluctance to involve pain specialists. The lack of spontaneous reporting of pain by PWH, despite using pain relief, highlights the need for clinicians to actively ask patients about any pain they may be experiencing.

Plasma phospholipid dysregulation in patients with cystathionine-ß synthase deficiency.

BACKGROUND & AIMS: Patients with cystathionine ß-synthase deficiency (CBSD) exhibit high circulating levels of homocysteine and enhanced lipid peroxidation. We have characterized the plasma lipidome in CBSD patients and related lipid abnormalities with reactions underlying enhanced homocysteine levels. METHODS AND RESULTS: Using an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, plasma lipids were determined with an untargeted lipidomics approach in 11 CBSD patients and 11 matched healthy subjects (CTRL). Compared to CTRL, CBSD patients had a higher medium and long-chain polyunsaturated fatty acids (PUFA) content in phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (LPE) species (p < 0.02), and depletion of phosphatidylcholine (PC; p = 0.02) and of lysophosphatidylcholine (LPC; p = 0.003) species containing docosahexaenoic acid (DHA), suggesting impaired phosphatidylethanolamine-N-methyltransferase (PEMT) activity. PEMT converts PE into PC using methyl group by S-adenosylmethionine (SAM) thus converted in S-adenosylhomocysteine (SAH). Whole blood SAM and SAH concentrations by liquid chromatography tandem mass spectrometry were 1.4-fold (p = 0.015) and 5.3-fold (p = 0.003) higher in CBSD patients than in CTRL. A positive correlation between SAM/SAH and PC/PE ratios (r = 0.520; p = 0.019) was found. CONCLUSIONS: A novel biochemical abnormality in CBSD patients consisting in depletion of PC and LPC species containing DHA and accumulation of PUFA in PE and LPE species is revealed by this lipidomic approach. Changes in plasma SAM and SAH concentrations are associated with such phospholipid dysregulation. Given the key role of DHA in thrombosis prevention, depletion of PC species containing DHA in CBSD patients provides a new direction to understand the poor cardiovascular outcome of patients with homocystinuria.

Role of clinical and laboratory parameters for treatment choice in patients with inherited FVII deficiency undergoing surgical procedures: evidence from the STER registry.

Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with <3% FVII:C received a higher number of RT doses (8 vs. 2, P = 0·003) for a longer RT duration (3 days vs. 1 day, P = 0·001), with no difference in RT dose. Similarly, patients with a history of major bleeds received a higher number of RT doses (8·5 vs. 2-3, P = 0·013) for a longer RT duration (2 days vs. 1 day, P = 0·005) as compared to those with a history of minor bleeds or to asymptomatic patients. No difference in RT was found among major and minor surgical procedures. Overall, multivariate analysis showed that history of major bleeding was the only independent predictor of number of RT doses (ß = 0·352, P = 0·001) and RT duration (ß = 0·405, P = 0·018). Overall, a ≈20 µg/kg perioperative RT was efficacious in 95·5% of cases. The infusion should be repeated ≈8 times in high-risk subsets (i.e. patients with a history of major bleeding).

The anti-CD20 monoclonal antibody rituximab to treat acquired haemophilia A.

BACKGROUND: Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against naturally occurring factor VIII (FVIII). Although about half of cases are idiopathic, AHA may be associated with several non-neoplastic conditions, autoimmune disorders, as well as haematological malignancies, such as chronic lymphocytic leukaemia and lymphoma. The long-term suppression of inhibitors is one of the mainstays of the treatment of AHA. Apart from standard immunosuppressive treatments, rituximab has been proven to be effective in AHA. MATERIALS AND METHODS: The aim of this review is to provide a systematic description of data available in the literature on this topic. To do so, we performed a search using the indexed online database Medline/PubMed, without temporal limits, matching the words "rituximab" and "acquired h(a)emophilia". Furthermore, additional published studies were identified in the reference list of the publications found in PubMed. RESULTS: The review of the literature confirms that rituximab may be a safe and useful treatment for AHA. DISCUSSION: Although rituximab is not a standard therapy for AHA, it may be useful in resistant cases. However, the definitive place of this monoclonal antibody in the therapeutic strategy for AHA (first or second-line, alone or in combination with other drugs) remains to be determined more precisely and warrants further investigation.

IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII.

The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.

Human megakaryocytes confer tissue factor to a subset of shed platelets to stimulate thrombin generation.

Tissue factor (TF), the main activator of the blood coagulation cascade, has been shown to be expressed by platelets. Despite the evidence that both megakaryocytes and platelets express TF mRNA, and that platelets can make de novo protein synthesis, the main mechanism thought to be responsible for the presence of TF within platelets is through the uptake of TF positive microparticles. In this study we assessed 1) whether human megakaryocytes synthesise TF and transfer it to platelets and 2) the contribution of platelet-TF to the platelet hemostatic capacity. In order to avoid the cross-talk with circulating microparticles, we took advantage from an in vitro cultured megakaryoblastic cell line (Meg-01) able to differentiate into megakaryocytes releasing platelet-like particles. We show that functionally active TF is expressed in human megakaryoblasts, increased in megakaryocytes, and is transferred to a subset of shed platelets where it contributes to clot formation. These data were all confirmed in human CD34pos-derived megakaryocytes and in their released platelets. The effect of TF silencing in Meg-megakaryoblasts resulted in a significant reduction of TF expression in these cells and also in Meg-megakaryocytes and Meg-platelets. Moreover, the contribution of platelet-TF to the platelet hemostatic capacity was highlighted by the significant delay in the kinetic of thrombin formation observed in platelets released by TF-silenced megakaryocytes. These findings provide evidences that TF is an endogenously synthesised protein that characterises megakaryocyte maturation and that it is transferred to a subset of newly-released platelets where it is functionally active and able to trigger thrombin generation.

Haemostatic and fibrinolytic changes in obese subjects undergoing bariatric surgery: the effect of different surgical procedures.

BACKGROUND: Little is known about effects of different bariatric surgery procedures on haemostatic and fibrinolytic parameters. MATERIAL AND METHODS: Consecutive obese subjects undergoing gastric bypass (GBP) or sleeve gastrectomy (SG) were enrolled. In all patients, levels of haemostatic factors (FII, FVII, FVIII, FIX, FX, vWF, fibrinogen), fibrinolytic variables (PAI-1, t-PA and D-dimer) and natural anticoagulants (AT, protein C and protein S) were evaluated before and 2 months after surgery. RESULTS: A total of 77 GBP and 79 SG subjects completed the study. At baseline no difference in coagulation parameters was found between the two groups. After both GBP and SG, subjects showed significant changes in haemostatic and fibrinolytic variables and in natural anticoagulant levels. The Δ% changes in FVII, FVIII, FIX, vWF, fibrinogen, D-dimer, protein C and protein S levels were significantly higher in subjects who underwent GBP than in those who underwent SG. Multivariate analysis confirmed that GBP was a predictor of higher Δ% changes in FVII (ß=0.268, p=0.010), protein C (ß=0.274, p=0.003) and protein S (ß=0.297, p<0.001), but not in all the other variables. Following coagulation factor reduction, 31 subjects (25.9% of GBP and 13.9% of SG; p=0.044) showed overt FVII deficiency; protein C deficiency was reported by 34 subjects (32.5% of GBP vs 11.4% of SG, p=0.033) and protein S deficiency by 39 (37.6% of GBP vs 12.6% of SG, p=0.009). Multivariate analyses showed that GBP was associated with an increased risk of deficiency of FVII (OR: 3.64; 95% CI: 1.73-7.64, p=0.001), protein C (OR: 4.319; 95% CI: 1.33-13.9, p=0.015) and protein S (OR: 5.50; 95% CI: 1.71-17.7, p=0.004). DISCUSSION: GBP is associated with an increased risk of post-operative deficiency in some vitamin K-dependent coagulation factors. Whereas such deficiency is too weak to cause bleeding, it is significant enough to increase the risk of thrombosis.

Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis.

OBJECTIVE: The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation. APPROACH AND RESULTS: We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE. CONCLUSIONS: Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia.

Homocysteine is metabolized to methionine by the action of 5,10 methylenetetrahydrofolate reductase (MTHFR). Alternatively, by the transulfuration pathway, homocysteine is transformed to hydrogen sulphide (H2S), through multiple steps involving cystathionine ß-synthase and cystathionine γ-lyase. Here we have evaluated the involvement of H2S in the thrombotic events associated with hyperhomocysteinemia. To this purpose we have used platelets harvested from healthy volunteers or patients newly diagnosed with hyperhomocysteinemia with a C677T polymorphism of the MTHFR gene (MTHFR++). NaHS (0.1-100 µM) or l-cysteine (0.1-100 µM) significantly increased platelet aggregation harvested from healthy volunteers induced by thrombin receptor activator peptide-6 amide (2 µM) in a concentration-dependent manner. This increase was significantly potentiated in platelets harvested from MTHFR++ carriers, and it was reversed by the inhibition of either cystathionine ß-synthase or cystathionine γ-lyase. Similarly, in MTHFR++ carriers, the content of H2S was significantly higher in either platelets or plasma compared with healthy volunteers. Interestingly, thromboxane A2 production was markedly increased in response to both NaHS or l-cysteine in platelets of healthy volunteers. The inhibition of phospholipase A2, cyclooxygenase, or blockade of the thromboxane receptor markedly reduced the effects of H2S. Finally, phosphorylated-phospholipase A2 expression was significantly higher in MTHFR++ carriers compared with healthy volunteers. In conclusion, the H2S pathway is involved in the prothrombotic events occurring in hyperhomocysteinemic patients.

Acquired inhibitors of coagulation factors: part I-acquired hemophilia A.

Acquired hemophilia A (AHA) is a rare, but often severe, bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). AHA occurs more frequently in the elderly and in association with several conditions, such as malignancies, autoimmune diseases, postpartum, or drug exposure; however, about half of the cases remain idiopathic. At variance with congenital hemophilia, where hemarthroses are the most common bleeding symptoms, hemorrhages in AHA involving soft tissues (muscle, skin) are more frequently reported. AHA is diagnosed in patients: with negative personal or family bleeding history; in which prolonged activated partial thromboplastin time is not corrected after mixing and incubating equal volumes of patient and normal plasma for ~2 hours at 37°C; FVIII levels are reduced; and a specific FVIII-inhibiting activity is detected. Prompt recognition and treatment of AHA are mandatory, as inadequate management and complications of the disease are associated with high mortality rates. Therapeutic approaches should aim to control acute bleeds, eradicate FVIII-autoantibody production, treat associated diseases, and when possible, eliminate them. Present knowledge about this often overlooked and challenging condition has significantly increased following establishment of recent national and international studies, as will also be reviewed in this article.

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence-based approaches.

Immune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors in severe haemophilia A patients. Thirty years experience has shown high success rates (60-80%) with heterogeneous dose regimens and has led to the identification of clinical features that define the patients' prognostic profile. Children with recently diagnosed inhibitors are the best candidates for ITI and adequate management may further contribute to improve the short- and long-term ITI outcome. In these patients inhibitor eradication represents a cost-effective option because it enables the restoration of FVIII prophylaxis and consequently prevents arthropathy development. Adults with long-standing inhibitors often show bad predictors of ITI outcome, however, ITI may be considered as a suitable and cost-effective approach in cases with frequent bleeds that are not satisfactorily controlled by by-passing treatment and/or when orthopaedic surgery is needed. Optimal ITI regimens should be established in these different settings and randomized trials are addressing these issues. This article reviews the available literature evidence and clinical implications with current recommendations on ITI management, and highlights the issues still unsolved.

Homocysteine and arterial thrombosis: Challenge and opportunity.

The correlation between homocysteine and vascular disease has been assessed in several clinical studies that demonstrated that elevation of plasma total homocysteine (tHcy) was an independent risk factor for atheriosclerotic disease. Major advances of homocysteine metabolism disorders have been made during the last few years, encompassing the rare homozygous enzyme deficiencies, as well as more common milder abnormalities. In experimental and clinical studies, a homocysteine-mediated oxidant stress has been shown to trigger platelet activation, in turn leading to a tendency to thrombosis, in patients with severe hyperhomocysteinaemia. Likewise, the hypomethylation hypothesis on acquired hyperhomocysteinaemia (chronic renal disease) and the interrelationship between hyperhomocysteinaemia and impaired fibrinolysis, have added further biological plausibility to the role for hyperhomocysteinaemia in vascular medicine. However, whether hyperhomocysteinaemia is causal or a marker of vascular disease, and whether plasma tHcy is only an indicator of the metabolic status remains to be clarified. The role of the intake of some vitamins (folic acid, vit.B12, vit.B6) on cardiovascular disease (CVD) is poorly understood: in spite of the lowering of homocysteine (Hcy) levels, vitamin supplementation failed to exert significant effects on cardiovascular risk. On the other hand, although some lipid-modifying treatments increase Hcy levels in diabetics, there is no evidence that this attenuates the beneficial effects of such treatments on the cardiovascular risk. Because of these uncertainties in the area, the data available do not provide support for routine screening and treatment for elevated Hcy to prevent CVD.

Glanzmann's thrombasthenia (defective platelet integrin alphaIIb-beta3): proposals for management between evidence and open issues.

Glanzmann's Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder, characterized by a quantitative or qualitative defect of platelet surface alpha(IIb)-beta(3) integrin. Presently, no specific guideline/algorithm for clinical management for GT is available. Due to the rarity and heterogeneity of inherited platelet abnormalities, recommendations and guidelines are based on reports from opinions and clinical experience of panel of experts, and refer to the general management of platelet disorders. Based on the limited evidence in the area and on the strategies in clinical settings of inherited/acquired platelet defects, proposals for management of minor bleeding, moderate/major bleeding unresponsive to conservative management, major surgery, minor surgery and dental procedures for GT patients without, or with anti-platelet isoantibodies are reported. In addition to life-style advices and continuous patient education programs, when and how to employ/combine local measures, antifibrinolytic agents, hormone treatment, platelet transfusions and recombinant activated Factor VII is described. The prospective collection of treatments in GT patients recently established (Glanzmann's Thrombasthenia Registry, GTR), based on a careful definition of clinical settings and outcomes, is likely to provide newer insight for optimising clinical management in GT.

Increased troponin I predicts in-hospital occurrence of hemodynamic instability in patients with sub-massive or non-massive pulmonary embolism independent to clinical, echocardiographic and laboratory information.

INTRODUCTION: Whether in patients with acute central sub-massive or non-massive pulmonary embolism, mild troponin I increase (>0.03 mug/L) predicts in-hospital occurrence of hemodynamic instability and death independent to prognostically relevant clinical, laboratory and echocardiographic information is not fully established. METHODS AND RESULTS: We evaluated consecutively patients admitted to the Emergency Room for pulmonary embolism; those in stable hemodynamics in whom central pulmonary embolism was confirmed by spiral-computed tomography were recruited. All participants underwent standardized study protocol, including clinical and diagnostic evaluation for assessment of severity of pulmonary embolism; therapy was established accordingly; troponin I was measured, but treatment protocol was not affected by knowledge of troponin I levels. Of 90 patients enrolled in the study, 33 (37%) developed hemodynamic instability during hospitalization (on average, 90 h +/-20 from admission). Troponin I was >0.03 microg/L in 56% of the study population at admission, and predicted occurrence of hemodynamic instability during hospitalization (adjusted hazard ratio 9.8, 95% confidence interval 1.2-79.2), independent to age, gender, co-morbidity, systolic blood pressure, CK-MB, echocardiographic right ventricular dysfunction and other covariates. Twelve patients died during hospitalization (mean time to event 107 h +/-24 from admission); troponin I >0.03 microg/L predicted mortality in univariate analysis, but not after accounting for age, sex and clinical variables. Nevertheless, higher troponin as continuous variable correlated with higher likelihood of in-hospital death (adjusted likelihood ratio 2.2/microg/L, 95% confidence interval 1.1-4.3) in multivariate analysis. In a further multivariate model, CK-MB predicted mortality independent of covariates and troponin I. CONCLUSIONS: In patients with acute central sub-massive or non-massive pulmonary embolism, even mild increase in troponin I >0.03 microg/L may provide relevant short-term prognostic information independent to clinical, laboratory and echocardiographic data.