Valeria Raparelli

Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?

Patients with cirrhosis can have abnormalities in laboratory tests reflecting changes in primary haemostasis, including bleeding time, platelet function tests, markers of platelet activation, and platelet count. Such changes have been considered particularly relevant in the bleeding complications that occur in cirrhosis. However, several studies have shown that routine diagnostic tests, such as platelet count, bleeding time, PFA-100, thromboelastography are not clinically useful to stratify bleeding risk in patients with cirrhosis. Moreover, treatments used to increase platelet count or to modulate platelet function could potentially do harm. Consequently the optimal management of bleeding complications is still a matter of discussion. Moreover, in the last two decades there has been an increased recognition that not only bleeding but also thrombosis complicates the clinical course of cirrhosis. Thus, we performed a literature search looking at publications studying both qualitative and quantitative aspects of platelet function to verify which primary haemostasis defects occur in cirrhosis. In addition, we evaluated the contribution of qualitative and quantitative aspects of platelet function to the clinical outcome in cirrhosis and their therapeutic management according to the data available in the literature. From the detailed analysis of the literature, it appears clear that primary haemostasis may not be defective in cirrhosis, and a low platelet count should not necessarily be considered as an automatic index of an increased risk of bleeding. Conversely, caution should be observed in patients with severe thrombocytopenia where its correction is advised if bleeding occurs and before invasive diagnostic and therapeutic procedures.

Incidence of Myocardial Infarction and Vascular Death in Elderly Patients With Atrial Fibrillation Taking Anticoagulants: Relation to Atherosclerotic Risk Factors

BACKGROUND Recent findings suggest that patients with atrial fibrillation (AF), in addition being at thromboembolic risk, are at risk of myocardial infarction (MI). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants. METHODS We prospectively followed up 1,019 patients with AF for a median of 33.7 months (3,223 person-years). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events (CVEs) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death. RESULTS The mean age of the patients was 73.2 years, and 43.8% were women. At follow-up, 111 CVEs (3.43%/y) had occurred: 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks (0.96%/y) were recorded. Patients experiencing CVEs were older (P < .001) and had a higher prevalence of metabolic syndrome (MetS) (P = .005), heart failure (P = .001), and prior cardiac (P < .001) and cerebrovascular events (P < .001). On a Cox proportional hazard analysis, age (hazard ratio [HR], 1.083; 95% CI, 1.053-1.113; P < .001), smoking (HR, 2.158; 95% CI, 1.193-3.901; P = .011), history of cerebrovascular (HR, 1.704; 95% CI, 1.119-2.597; P = .013) and cardiac (HR, 1.658; 95% CI, 1.105-2.489; P = .015) events, MetS (HR, 1.663; 95% CI, 1.107-2.499; P = .014), heart failure (HR, 1.584; 95% CI, 1.021-2.456; P = .040), and male sex (HR, 1.499; 95% CI, 1.010-2.223; P = .044) predicted CVEs. CONCLUSIONS Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01882114; URL: www.clinicaltrials.gov.

NADPH oxidase-mediated platelet isoprostane over-production in cirrhotic patients: implication for platelet activation

In patients with cirrhosis conflicting findings, inherent to platelet function and its clinical implication, are still matters of discussion. Cirrhosis is characterized by enhanced production of isoprostanes, index of oxidative stress in vivo, that is known to stem from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2)‐generating oxidative stress and elicit platelet activation.

Intravenous Ascorbic Acid Infusion Improves Myocardial Perfusion Grade During Elective Percutaneous Coronary Intervention. Relationship With Oxidative Stress Markers

OBJECTIVES Our goal was to explore whether antioxidant vitamin C infusion is able to affect the microcirculation perfusion in patients undergoing elective percutaneous coronary intervention for stable angina. BACKGROUND Periprocedural myocardial injury in the setting of elective percutaneous coronary intervention is associated with increased risk of death, recurrent infarction, and revascularization at follow-up. Despite excellent epicardial blood flow, impaired microcirculatory reperfusion may persist and increases the risk of vascular recurrences. Post-percutaneous coronary intervention induced-oxidative stress is one of the potential mechanisms accounting for impaired perfusion. METHODS Fifty-six patients were enrolled in a prospective, single-center, randomized study comparing 1 g vitamin C infusion (16.6 mg/min, over 1 h before percutaneous coronary intervention) versus placebo. RESULTS At the baseline, Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade <2 was observed in 89% and in 86% of patients randomized to the placebo or vitamin C infusion group, respectively (p > 0.05). After percutaneous coronary intervention, these percentages decreased in the placebo group (32%) and in greater measure in the vitamin C group (4%, p < 0.01). Complete microcirculatory reperfusion (TIMI myocardial perfusion grade = 3) was achieved in 79% of the vitamin C-treated group compared with 39% of the placebo group (p < 0.01); 8-hydroxy-2-deoxyguanosine (p < 0.002) and 8-iso-prostaglandin F(2alpha) (p < 0.02) plasma levels significantly increased in the placebo group while they were significantly reduced in the vitamin C-treated group (p < 0.0001). TIMI myocardial perfusion grade changes from the baseline showed significant correlation with 8-hydroxy-2-deoxyguanosine (p < 0.006) or 8-iso-prostaglandin F(2alpha) (p < 0.01) plasma levels changes. CONCLUSIONS In patients undergoing elective percutaneous coronary intervention, impaired microcirculatory reperfusion is improved by vitamin C infusion suggesting that oxidative stress is implicated in such a phenomenon.

Chronotype, gender and general health.

ABSTRACT Background: Light–dark alternation has always been the strongest external circadian “zeitgeber” for humans. Due to its growing technological preference, our society is quickly transforming toward a progressive “eveningness” (E), with consequences on personal circadian preference (chronotype), depending on gender as well. The aim of this study was to review the available evidence of possible relationships between chronotype and gender, with relevance on disturbances that could negatively impact general health, including daily life aspects. Methods: Electronic searches of the published literature were performed in the databases MEDLINE and Web of Science, by using the Medical Subject Heading (MeSH), when available, or other specific keywords. Results: Results were grouped into four general areas, i.e. (a) “General and Cardiovascular Issues”, (b) “Psychological and Psychopathological Issues”, (c) “Sleep and Sleep-Related Issues” and (d) “School and School-Related Issues”. (a) E is associated with unhealthy and dietary habits, smoking and alcohol drinking (in younger subjects) and, in adults, with diabetes and metabolic syndrome; (b) E is associated with impulsivity and anger, depression, anxiety disorders and nightmares (especially in women), risk taking behavior, use of alcohol, coffee and stimulants, psychopathology and personality traits; (c) E has been associated, especially in young subjects, with later bedtime and wake-up time, irregular sleep–wake schedule, subjective poor sleep, school performance and motivation, health-related quality of life; (d) E was associated with lowest mood and lower overall grade point average (especially for women). Conclusions: Eveningness may impact general health, either physical or mental, sleep, school results and achievements, especially in younger age and in women. The role of family support is crucial, and parents should be deeply informed that abuse of technological devices during night hours may lead to the immature adjustment function of children’s endogenous circadian pacemakers.

The coagulopathy of chronic liver disease: Is there a causal relationship with bleeding? Yes

Variceal hemorrhage is a major cause of death in patients with cirrhosis. Much still could be performed in clinical practice to reduce the risk for bleeding in cirrhotic patients and accurate predictive rules should be provided for early recognition of high-risk patients. Liver cirrhosis patients present a complex hemostatic dysfunction with prolongation of bleeding time, chronic coagulation activation, and secondary hyperfibrinolysis. Therefore, liver failure determines an acquired coagulopathy that has been considered to be one potential underlying mechanism of bleeding. Endotoxemia may play a pivotal role in activating clotting system in portal and systemic circulation and it could represent a common mechanism accounting for portal vein thrombosis, systemic hyperfibrinolysis and eventually gastrointestinal bleeding. Nevertheless, clinical trials should also be planned to investigate the causal relationship between acquired coagulopathy and bleeding in patients with chronic liver disease.

Low‐grade endotoxemia and platelet activation in cirrhosis

Patients with cirrhosis may display impaired or enhanced platelet activation, but the reasons for these equivocal findings are unclear. We investigated if bacterial lipopolysaccharide (LPS) is implicated in platelet activation. In a cross‐sectional study, conducted in an ambulatory care clinic and hospital, comparing 69 cirrhosis patients and 30 controls matched for sex, age, and atherosclerotic risk factors, serum levels of LPS, soluble cluster of differentiation 40 ligand and p‐selectin (two markers of platelet activation), and zonulin (a marker of gut permeability) were investigated. Ex vivo and in vitro studies were also performed to explore the effect of LPS on platelet activation. Compared to controls, cirrhosis patients displayed higher serum levels of LPS (6.0 [4.0‐17.5] versus 57.4 [43.4‐87.2] pg/mL, P < 0.0001), soluble cluster of differentiation 40 ligand (7.0 ± 2.2 versus 24.4 ± 13.3 ng/mL, P < 0.0001), soluble p‐selectin (14.2 ± 4.05 versus 33.2 ± 15.2 ng/mL, P < 0.0001), and zonulin (1.87 ± 0.84 versus 2.54 ± 0.94 ng/mL, P < 0.006). LPS significantly correlated with zonulin (r = 0.45, P < 0.001). Ex vivo studies showed that platelets from cirrhosis patients were more responsive to the agonists independently from platelet count; this phenomenon was blunted by incubation with an inhibitor of Toll‐like receptor 4. In vitro study by normal platelets showed that LPS alone (50‐150 pg/mL) did not stimulate platelets but amplified platelet response to the agonists; Toll‐like receptor 4 inhibitor blunted this effect. Conclusion: LPS may be responsible for platelet activation and potentially contributes to thrombotic complications occurring in cirrhosis. (Hepatology 2017;65:571‐581).

Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: A pilot study

BackgroundAim of this pilot study is to examine the effects of myo-inositol administration on ovarian response and oocytes and embryos quality in non PolyCystic Ovary Syndrome (PCOS) patients undergoing multiple follicular stimulation and in vitro insemination by conventional in vitro fertilization or by intracytoplasmic sperm injection.MethodsOne hundred non-PCOS women aged <40 years and with basal FSH <10 mUI/ml were down-regulated with triptorelin acetate from the mid-luteal phase for 2 weeks, before starting the stimulation protocol for oocytes recovery. All patients received rFSH, at a starting dose of 150 IU for 6 days. The dose was subsequently adjusted according to individual response. Group B (n = 50) received myo-inositol and folic acid for 3 months before the stimulation period and then during the stimulation itself. Group A (n-50) received only folic acid as additional treatment in the 3 months before and through treatment.ResultsTotal length of the stimulation was similar between the two groups. Nevertheless, total amount of gonadotropins used to reach follicular maturation was found significantly lower in group B. In addition, the number of oocytes retrieved was significantly reduced in the group pretreated with myo-inositol. Clinical pregnancy and implantation rate were not significantly different in the two groups.ConclusionsOur findings suggest that the addition of myo-inositol to folic acid in non PCOS-patients undergoing multiple follicular stimulation for in-vitro fertilization may reduce the numbers of mature oocytes and the dosage of rFSH whilst maintaining clinical pregnancy rate. Further, a trend in favor of increased incidence of implantation in the group pretreated with myo-inositol was apparent in this study. Further investigations are warranted to clarify this pharmacological approach, and the benefit it may hold for patients.

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.

Comparison of efficacy of antiplatelet treatments for patients with claudication: A meta-analysis

It was the aim of the present study to investigate if antiplatelet treatment reduced cardiovascular events in patients with claudication and/or an ankle/brachial index (ABI)< or =0.99 and to analyse if specific antiplatelet treatment had a different impact on clinical outcome. We performed a meta-analysis of 29 clinical randomized trials on antiplatelet therapy for prevention of vascular death, myocardial infarction, and stroke in 10,735 peripheral artery disease patients. The primary end-point utilizing in the meta-analysis construction was Cardiovascular Adverse Event. We found 1,900 (17.70%) patients in trials with aspirin, 5,326 (49.61%) in those with thienopyridines, 2,324 (21.65%) in those with picotamide and 1,185 (11.04 %) in those with others antiplatelet drugs. A statistically significant effect of antiplatelet treatment [odds ratio (OR) 0.839; 95% confidence interval (CI) 0.729-0.965; p=0.014] was observed. There was a statistically significant reduction of clinical outcome [OR 0.779; 95% CI 0.639-0.950; p=0.014] in the thienopyridine-treated group vs. control. Patients treated with picotamide [OR 0.785; 95% CI 0.495-1.243; p=0.302] or aspirin [OR 0.847; 95%CI 0.653-1.097; p=0.084] showed reduced cardiovascular outcomes, that, however, did not reach significance. The study confirms that antiplatelet treatment reduces vascular outcome in claudicants. Significant reduction was observed with thienopyridines while data regarding aspirin and picotamide were inconclusive.