Gender-specific effects of capsiate supplementation on body weight and bone mineral density: a randomized, double-blind, placebo-controlled study in slightly overweight women.

INTRODUCTION: Overweight and obesity are highly prevalent conditions associated with premature morbidity and mortality worldwide. Capsiate, a nonpungent analogue of capsaicin, binds to TRP vanilloid 1 (TRPV1) receptor, which is involved in adipogenesis, and could be effective as a weight-lowering agent. METHODS: Eighteen slightly overweight women were enrolled in this randomized, double-blind, placebo-controlled study. Nine patients were included in the capsiate intervention group and received 9 mg/day of capsinoids and 9 patients received placebo for 8 weeks. All patients underwent weight and waist circumference assessment before and after treatment. Body composition and bone mineral density (BMD) were also detected by dual-energy X-ray absorptiometry (DXA). RESULTS: Fourteen patients completed the study. The treatment with capsiate or placebo for 8 weeks was not associated with significant changes in weight or waist circumference. After treatment, there was a significant improvement in BMD values measured at the spine in the capsiate group (1.158 vs 1.106 g/cm2, + 4.7%; p = 0.04), but not in the group treated with placebo. Similarly, the capsiate group showed a 9.1% increase (p = 0.05) in the adipose tissue and an 8.5% decrease in lean mass measured at the supraclavicular level, whereas these changes were not statistically significant in the placebo group. CONCLUSIONS: Treatment with capsiate for 8 weeks led to negligible changes in body weight in a small sample of slightly overweight women, but our findings suggest a potential effect of capsaicin on bone metabolism in humans.

Testosterone-to-estradiol ratio and platelet thromboxane release in ischemic heart disease: the EVA project.

BACKGROUND: Data on the interplay between sexual hormones balance, platelet function and clinical outcomes of adults with ischemic heart disease (IHD) are still lacking. OBJECTIVE: To assess the association between the Testosterone (T)-to-Estradiol (E2) Ratio (T/E2) and platelet activation biomarkers in IHD and its predictive value on adverse outcomes. METHODS: The EVA study is a prospective observational study of consecutive hospitalized adults with IHD undergoing coronary angiography and/or percutaneous coronary interventions. Serum T/E2 ratios E2, levels of thromboxane B2 (TxB2) and nitrates (NO), were measured at admission and major adverse events, including all-cause mortality, were collected during a long-term follow-up. RESULTS: Among 509 adults with IHD (mean age 67 ± 11 years, 30% females), males were older with a more adverse cluster of cardiovascular risk factors than females. Acute coronary syndrome and non-obstructive coronary artery disease were more prevalent in females versus males. The lower sex-specific T/E2 ratios identified adults with the highest level of serum TxB2 and the lowest NO levels. During a median follow-up of 23.7 months, the lower sex-specific T/E2 was associated with higher all-cause mortality (HR 3.49; 95% CI 1.24-9.80; p = 0.018). In in vitro, platelets incubated with T/E2 ratios comparable to those measured in vivo in the lowest quartile showed increased platelet activation as indicated by higher levels of aggregation and TxB2 production. CONCLUSION: Among adults with IHD, higher T/E2 ratio was associated with a lower long-term risk of fatal events. The effect of sex hormones on the platelet thromboxane release may partially explain such finding.

The phosphodiesterase 5 inhibitor sildenafil decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: in vivo and in vitro evidence.

PURPOSE: Interleukin (IL)-8 is a proinflammatory C-X-C chemokine involved in inflammation underling cardiac diseases, primary or in comorbid condition, such diabetic cardiomyopathy (DCM). The phosphodiesterase type 5 inhibitor sildenafil can ameliorate cardiac conditions by counteracting inflammation. The study aim is to evaluate the effect of sildenafil on serum IL-8 in DCM subjects vs. placebo, and on IL-8 release in human endothelial cells (Hfaec) and peripheral blood mononuclear cells (PBMC) under inflammatory stimuli. METHODS: IL-8 was quantified: in sera of (30) DCM subjects before (baseline) and after sildenafil (100 mg/day, 3-months) vs. (16) placebo and (15) healthy subjects, by multiplatform array; in supernatants from inflammation-challenged cells after sildenafil (1 µM), by ELISA. RESULTS: Baseline IL-8 was higher in DCM vs. healthy subjects (149.14 ± 46.89 vs. 16.17 ± 5.38 pg/ml, p < 0.01). Sildenafil, not placebo, significantly reduced serum IL-8 (23.7 ± 5.9 pg/ml, p < 0.05 vs. baseline). Receiver operating characteristic (ROC) curve for IL-8 was 0.945 (95% confidence interval of 0.772 to 1.0, p < 0.01), showing good capacity of discriminating the response in terms of drug-induced IL-8 decrease (sensitivity of 0.93, specificity of 0.90). Sildenafil significantly decreased IL-8 protein release by inflammation-induced Hfaec and PBMC and downregulated IL-8 mRNA in PBMC, without affecting cell number or PDE5 expression. CONCLUSION: Sildenafil might be suggested as potential novel pharmacological tool to control DCM progression through IL-8 targeting at systemic and cellular level.

Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103/µl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.

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.

Misdiagnosis in fibromyalgia: a multicentre study.

BACKGROUND: Fibromyalgia (FM) is the second most common cause of visits to rheumatologists after osteoarthritis, and may be difficult to diagnose in many patients. It is associated with various rheumatic disorders such as rheumatoid arthritis, spondyloarthropathies (SpA) and connective tissue disease (CTD), and a late diagnosis or misdiagnosis is a common and underestimated problem. OBJECTIVES: The aim of this study was to investigate the 'underdiagnosis' of FM, and which rheumatic diseases tend to be confused with it. METHODS: The following data were collected at baseline: symptoms, disease duration, physical examination findings, previous and current investigations and management, laboratory tests, tender point count, tender and swollen joint counts, and spinal pain. The clinimetric evaluation included the Fibromyalgia Impact Questionnaire (FIQ) and Fibromyalgia Assessment Status (FAS). RESULTS: The study population consisted of 427 outpatients (418 females and 9 males; mean age 49.3 years; mean disease duration 8.5 years). Fifty-seven patients (13.3%) had been previously misdiagnosed as having other musculoskeletal disorders (MSDs); 370 patients had been previous correctly diagnosed as having FM, or were diagnosed as having it during the course of the study. The FM and MSD groups were comparable in terms of demographic data and referral patterns. Disease duration was longer and the erythrocyte sedimentation rate was higher in the MSD patients, who also had less severe FIQ and lower pain visual analogue scale scores. Moreover, the FIQ and FAS scores correlated in the MS group. CONCLUSIONS: The findings of this study suggest that, although FM is a wellknown clinical entity, differential diagnosis with SpA, CTD and inflammatory arthritis can still be a challenge for rheumatologists and general practitioners.

E-learning course improves knowledge in tobacco dependence, electronic nicotine delivery systems and heat-not-burn products in Medical School students.

BACKGROUND: Adequate training in tobacco, nicotine dependence and treatment is lacking in Medical School education. With the rise in popularity of electronic alternatives to cigarettes, future physicians should also be provided with the more recent scientific evidence on these products during their undergraduate studies. We introduced an e-learning course for Medical School students and assessed its effec-tiveness of increasing knowledge on these topics. METHODS: We developed 16 didactic modules divided in 3 courses: tobacco dependence (TDI), treating tobacco dependence (TDII) and electronic products and tobacco control (TDIII). The course was offered to 4th, 5th, and 6th year Medical School students in Italy. To assess learning outcomes, we examined the pre- to post- changes in knowledge scores associated with each course. Paired and independent samples t-tests were performed overall, and among smokers and non-smokers separately. RESULTS: A total of 1318 students completed at least one of the courses; 21% were self-reported smokers. A significant increase in knowledge was observed at the end of TDI (pre-course: 52.1±15.9, post-course: 79.9±13.5, p<0.001), TDII (pre-course: 52.5±13.0, post-course: 66.5±12.0, p<0.001) and TDIII (pre-course: 52.2±15.3, post-course: 76.1±17.7, p<0.001). Smokers showed significantly lower improvements compared to non-smokers. CONCLUSIONS: The e-learning course was effective in increasing knowledge about tobacco dependence, treatments, and electronic ni-cotine products in advanced medical students. Given the fundamental role for healthcare practitioners in encouraging and assisting people in quitting smoking, e-learning may be a useful tool in providing up-to-date and standardized training in the area during Medical School.

Impact of cardiovascular risk factors on incidence and severity of Retinal Vein Occlusion.

PURPOSE: Retinal Vein Occlusion (RVO) is a thrombotic process affecting retinal veins. The purpose of this research is to study demographic characteristics and prevalence of cardiovascular comorbidities among subjects affected by RVO. In addition, authors explore the role of each variable in determining occlusion type and severity. SUBJECTS, MATERIALS AND METHODS: This was a prospective observational study recruiting subjects affected by RVO and secondary macular edema. Exclusion criteria included pre-existing macular edema, recent ocular surgery (<6 months), pregnancy, diagnosis other than RVO, diabetes mellitus type I, any systemic pathology that significantly reduced life expectancy. Each participant was studied through a comprehensive medical history, cardiovascular assessment, blood testing, ocular exam, and macular OCT imaging. RESULTS: A total of 145 eyes, 145 participants, thereof 80 males (55%) and 65 females. (45%) Mean age: 62.5 ± 14.3 SD. 61 eyes (42%) were affected by CRVO and 84 eyes (58%) by BRVO. No statistically significant differences were noted between genders. Hypertension was very prevalent (63%). Dyslipidemia was more associated with BRVO (p = 0.044). Subjects with hypertension had a mean central macular thickness (CMT) of 643 µm against a mean of 489 µm of those without hypertension. (p < 0.05). No other variable was associated with macular edema severity. CONCLUSIONS: Older age and hypertension are strong risk factors for RVO. Dyslipidemia was strongly associated with BRVO. (p=0.044) Hypertension was not only associated with RVO incidence, but also with its severity. In fact, hypertensive subjects had significantly worse macular edema.

Knowledge of nicotine dependence and treatment in clinical practice improved after an e-learning course among medical students.

OBJECTIVE: Tobacco smoking is the leading cause of preventable death in developed countries and smokers should be encouraged to quit. Physicians are instrumental in this, but recent reports suggest inadequate training in medical school. We aimed to assess the knowledge of nicotine dependence and its treatment among Italian medical students. STUDY DESIGN: Prospective observational study. METHODS: We developed an online course consisting of 11 Didactic Modules (6 for Tobacco Dependence I, TDI, and 5 for TDII) on nicotine dependence and treatment. The course was administered to 4th and 5th year medical students in Italy in Academic Years 2016-17 (Course A) and 2017-18 (Course B). A validated questionnaire was used before and after each part in order to measure knowledge of smoking epidemiology, health effects and benefits of giving up smoking ("Score 1", TDI), and effectiveness of cessation treatments ("Score 2", TDII). RESULTS: 324 students took both TDI and TDII and completed all questionnaires (Course A, n = 245; Course B, n = 79). 55 students were current smokers (17%). A significant increase in score 1 and 2 was observed at the end of both TDI (pre-course 47.2±13.1, post-course 66.0±12.3, p <0.0001) and TDII (pre-course 55.6±11.5, post-course 68.1±10.9, p <0.0001). The prevalence of students wishing for a smoke-free medical school significantly increased between the beginning of TDI (74.4%, 241/324) and the end of TDII (88%, 285/324; p <0.0001). CONCLUSIONS: This e-learning course has proven to be an effective tool in teaching students on nicotine dependence and treatment.

Contribution of platelet-derived CD40 ligand to inflammation, thrombosis and neoangiogenesis.

CD40-CD40L interactions have been involved in inflammation and thrombosis. Several diseases are characterized by inflammation, hypercoagulability and increased prevalence of thromboembolic events. In the past decade, a series of preclinical and clinical studies has provided more insight into the pathogenetic mechanisms linking inflammatory mediators to the activation and regulation of the haemostatic system. In particular, the study of CD40-CD40L interactions has greatly contributed to understanding the role of platelets in a variety of pathophysiological conditions, including atherothrombosis, immuno-inflammatory diseases and, possibly, cancer. A wide variety of preclinical and clinical studies have generated clinical interest in the use of CD40L as a prognostic marker of thrombotic risk. However, the use of sCD40L in clinical studies requires reliable methods. For the correct interpretation of results, clinical and research laboratories and physicians must be aware of the limitations of immunoassays for this cytokine, which underlines the need for standardization of preanalytic conditions. This review will focus on biochemical evidence of CD40L involvement in platelet activation, contribution of platelet-derived CD40L to inflammation, thrombosis and neoangiogenesis, and possible methodological pitfalls regarding the appropriate specimen and preparation for laboratory evaluation of blood soluble CD40L as a biomarker in various human diseases characterized by underlying inflammation, such as atherothrombosis, cancer and immuno-inflammatory diseases.

Kidney disease and venous thromboembolism: Does being woman make the difference?

The risk of venous thromboembolism (VTE) is increased across the spectrum of chronic kidney disease (CKD), from mild to more advanced CKD, and typically characterizes nephrotic syndrome (NS). VTE risk in patients with kidney disease may be due to underlying hemostatic abnormalities, including activation of pro-thrombotic factors, inhibition of endogenous anticoagulation systems, enhanced platelet activation and aggregation, and decreased fibrinolytic activity. The mechanisms involved differ depending on the cause of the kidney impairment (i.e. presence of NS or CKD stage). Sex and gender differences, as well as, environmental factors or comorbidities may play a modulating role; however, specific sex and gender data on this topic are still rare. The aim of the present review is to discuss the VTE risk associated with impairment of kidney function, the potential mechanism accounting for it and the impact of sex differences in this clinical setting.

Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia.

OBJECTIVE: The purpose of this study was to assess if simvastatin has an anti-inflammatory activity in patients with hypercholesterolemia. BACKGROUND: Simvastatin, an inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, reduced cardiovascular events in patients with myocardial infarction and hypercholesterolemia. METHODS: Sixteen patients with polygenic hypercholesterolemia were randomly allocated to diet (n = 8) or diet plus 20 mg/day simvastatin (n = 8) for eight weeks. Before and at the end of treatment period, lipid profile and monocyte expression of tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1beta) were measured. RESULTS: At baseline no difference in lipid profile and monocyte expression of TNF and IL-1beta were observed between the two groups. In patients allocated to diet alone, no change in lipid profile and monocyte expression of TNF and IL-1beta was seen. In patients with diet plus simvastatin, significant decreases of total cholesterol (-27%, p<0.02), low density lipoprotein-cholesterol (-33%, p<0.02), and monocyte expression of TNF (-49%, p<0.02) and IL-1beta (-35%, p<0.02) were observed. At the end of treatment period, patients treated with simvastatin had lower cholesterol and monocyte TNF and IL-1beta than did patients assigned to diet alone. CONCLUSION: This study suggests that simvastatin possesses anti-inflammatory activity via the inhibition of pro-inflammatory cytokines TNF and IL-1beta expressed by monocytes.

Platelet activation in type 2 diabetes mellitus.

The abnormal metabolic state that accompanies diabetes renders arteries susceptible to atherosclerosis, being capable of altering the functional properties of multiple cell types, including endothelium and platelets. In particular, an altered platelet metabolism and changes in intraplatelet signaling pathways may contribute to the pathogenesis of atherothrombotic complications of diabetes. A variety of mechanisms may be responsible for enhanced platelet aggregation. Among them, hyperglycemia may represent a causal factor for in vivo platelet activation, and may be responsible for nonenzymatic glycation of platelet glycoproteins, causing changes in their structure and conformation, as well as alterations of membrane lipid dynamics. Furthermore, hyperglycemia-induced oxidative stress is responsible for enhanced peroxidation of arachidonic acid to form biologically active isoprostanes, which represents an important biochemical link between impaired glycemic control and persistent platelet activation. Finally, increased oxidative stress is responsible for activation of transcription factors and expression of redox-sensitive genes leading to a phenotypic switch of endothelium toward an adhesive, pro-thrombotic condition, initial platelet activation, adhesion and subsequent platelet aggregate formation. All this evidence is strengthened by the results of clinical trials documenting the beneficial effects of metabolic control on platelet function, and by the finding that aspirin treatment may even be more beneficial in diabetic than in high-risk non-diabetic patients. Attention to appropriate medical management of diabetic patients will have great impact on long-term outcome in this high-risk population.

Leptin increase is associated with markers of the hemostatic system in obese healthy women.

BACKGROUND: Leptin, a hormone secreted by the adipose tissue, might be a link between obesity and increased morbidity for cardiovascular disease. Leptin exerts proinflammatory, pro-angiogenic actions by activating a specific receptor (Ob-Rb) which is expressed in human endothelial cells. Thus, a link may exist between leptin expression and endothelial dysfunction. OBJECTIVES: We sought to determine whether in obese women there is a correlation between leptin levels, endothelial perturbation and coagulative activation. METHODS: Circulating levels of leptin, von Willebrand Factor (VWF), factor (F)VIIa, prothrombin fragment 1 + 2 (F1+2), were measured in 51 non-diabetic, obese women and in 51 normal-weight subjects, using immunoenzymatic assays. RESULTS: Obese women had significantly higher levels of leptin, VWF, FVIIa, F1+2 compared with healthy women. Simple correlation coefficients showed significant correlation between leptin and either VWF, FVIIa, or F1+2 concentrations. A multiple linear regression analysis, performed to quantify further the relationship between leptin levels and the above-mentioned variables as well as the inflammatory marker C-reactive protein (CRP) and including age, body mass index (BMI), waist-hip ratio (WHR) and lipid parameters as potential confounders, revealed that only FVIIa and VWF were independently related to leptin levels. Reduction in adipose tissue after weight loss resulted in a decrease in both circulating leptin and endothelial and coagulative activation markers. CONCLUSIONS: We suggest that leptin might have pro-atherogenic effects in vivo, with a mechanism involving endothelial cell activation.

Inhibition of tissue-factor-mediated thrombin generation by simvastatin.

A previous study has shown that simvastatin reduces in vivo clotting activation and monocyte tissue factor (TF) expression. This effect, however, was only in part attributable to the reduction of serum cholesterol, suggesting that more than one mechanism may be involved. Furthermore, it was not investigated if the inhibition of clotting activation was dependent upon the reduced expression of monocyte TF. In order to assess if simvastatin directly affects clotting activation, we developed an in vitro method in which clotting system is activated by monocytes stimulated with LPS. Monocytes were prepared from blood taken from healthy volunteers or patients with hypercholesterolemia and incubated with heparinized plasma plus either simvastatin (0.01-10 microM) or medium as control. Samples were then stimulated with LPS (4 microg/ml) and after 6 h the rate of thrombin generation, assessed by prothrombin fragment (F) 1+2, was measured. In separate experiments, we measured the expression of TF by monocytes which were incubated with simvastatin and then stimulated with LPS. The study showed that compared to control, LPS-stimulated monocytes induced abundant formation of F1+2, which was inhibited by simvastatin in a dose-dependent manner. Simvastatin also inhibited dose dependently the monocyte expression of TF. This study suggests that simvastatin inhibits the rate of thrombin generation by directly interfering with the monocyte expression of TF.

Lipoprotein(a) serum levels in patients affected by chronic obstructive pulmonary disease.

A recent study has suggested that symptoms of chronic bronchitis predict the risk of coronary disease independently of the known major cardiovascular risk factors. High serum levels of lipoprotein(a) (Lp(a)) have also been considered as an independent risk factor for coronary heart disease. Therefore, the aim of the present study was to investigate the behaviour of Lp(a) in patients affected by chronic obstructive pulmonary disease (COPD). Serum levels of total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, apolipoprotein (Apo) B-100, and Lp(a) were measured in 90 COPD patients and in 90 normal subjects matched for age, sex and smoking habit. COPD patients showed lower serum levels of Apo B-100 (P<0.0001) and Lp(a) (P<0.003) compared to controls. Conversely, TC, HDL-C, LDL-C and triglycerides were similar between patients and controls. No significant differences were found in Apo B-100 and Lp(a) levels of patients either undergoing different therapeutic regimens, or with different smoking habits. A significant correlation between Apo B-100 and Lp(a) (rho=0.433, P<0. 0001) was also observed. In conclusion, COPD patients do not show an atherogenetic lipid pattern and their increased risk of coronary disease could be attributable to different factors, such as the ongoing hypercoagulability state often associated with COPD.

Association between high values of D-dimer and tissue-plasminogen activator activity and first gastrointestinal bleeding in cirrhotic patients. CALC Group.

Cirrhotic patients with decompensated state and high serum levels of fibrin(ogen) degradation products are at high risk of bleeding. The aim of this study was to further analyse the relationship between hyperfibrinolysis and bleeding in cirrhosis by measuring plasma values of D-dimer and tissue plasminogen activator (t-PA) activity. One-hundred-twelve cirrhotic patients with oesophageal varices and without previous upper-gastrointestinal bleeding entered the study and were followed-up for 3 years. Patients were considered to have hyperfibrinolysis if they concomitantly had high values of D-dimer and t-PA activity. During the follow-up 34 (30%) patients bled. They had more severe liver failure (p = 0.0001) and variceal size (p = 0.0031) and higher prevalence of ascites (p = 0.0003), varices with red signs and hyperfibrinolysis (p = 0.0001) than patients who did not bleed. Multivariate analysis disclosed hyperfibrinolysis as the only marker predictive of bleeding (Hazard Ratio = 42.5, p < 0.001). Our findings suggest that screening for hyperfibrinolysis may be useful to identify cirrhotic patients at risk of bleeding.

Hypercoagulability state in patients with chronic obstructive pulmonary disease. Chronic Obstructive Bronchitis and Haemostasis Group.

Since there is some clinical evidence that the clinical course of patients with chronic obstructive pulmonary disease (COPD) may be complicated by thrombosis in the pulmonary vessels, we studied whether a hypercoagulability state (HS) does occur in COPD. Plasma levels of prothrombin F1 + 2 fragment, a marker of thrombin generation, D-dimer, a marker of in vivo thrombin and plasmin activation, and fibrinogen were measured in 37 COPD patients and in 30 controls matched for sex and age. COPD patients had significantly higher values of F1 + 2 (p = 0.0001) and fibrinogen (p = 0.0005) than healthy subjects. The difference persisted after excluding smoking patients. F1 + 2 was not correlated with PaO2 (r = 0.02, p > 0.05) and PaCO2 (p = 0.12, p > 0.05). In six patients with stable COPD and F1 + 2 greater than 1.65 nM (mean + 2 SD of controls) subcutaneous calcium-heparin therapy (5000 IU t.i.d. for 15 days) significantly reduced F1 + 2 (p = 0.03) and PaCO2 (p = 0.01). This study shows that COPD patients have an ongoing prothrombotic state which could potentially account for thrombosis occurring in pulmonary vessels. The effect of calcium-heparin treatment on clotting system activation and blood gas may suggest this treatment as potential candidate for prospective study in COPD patients.

Ongoing prothrombotic state in the portal circulation of cirrhotic patients.

Portal thrombosis may complicate the clinical course of cirrhosis, but the pathophysiologic mechanism is unclear. Aim of the study was to evaluate the behavior of clotting system and endotoxemia in portal vein and in peripheral circulation of 11 cirrhotic patients undergoing transjugular port-systemic shunt (TIPS). Portal blood showed higher values of F1 + 2 [Median (range): 2.5 (1.1-5.3) vs. 1.1 (0.6-2.1) nM, p < 0.01], D-dimer [765 (184-1713) vs. 192 (64-813) ng/ml, p < 0.01] and endotoxemia [31 (16-47.2) vs. 13.7 (7.5-23.5) pg/ml, p < 0.01] than peripheral circulation. In the portal vein, all but one sample had F1 + 2 > 1.2 nM (upper limit of control values), all but one had D-dimer > 216 mg/dl (mean + 2 SD of controls) and 100% had values of endotoxemia > 9.6 pg/ml (upper limit of control values). Fibrinogen was lower in the portal circulation compared to peripheral circulation but the difference was not significant [85 (58-195) vs. 134 (75-244) mg/dl, p > 0.05]. Endotoxemia was directly correlated with F1 + 2 (Rho = 0.92 p < 0.006) and D-dimer (Rho = 0.93, p < 0.005). This study shows that an ongoing prothrombotic state is present in the portal circulation of cirrhotic patients and may play a pivotal role in the thrombotic episodes occurring in this clinical setting.

Clotting activation after transjugular intrahepatic portosystemic stent shunt.

BACKGROUND AND AIM: Aim of the study was to investigate the behaviour of clotting system in peripheral circulation of cirrhotic patients undergoing transjugular intrahepatic portosystemic stent shunt (TIPS). METHODS: Clotting variables and endotoxemia were measured 48 h and 30 days after TIPS in patients randomised to receive heparin or not. RESULTS: Forty-eight hours after TIPS, a significant increase of prothrombin fragment F1+2 was observed; such increase was less evident in patients given heparin. Similar findings were observed for endotoxemia, which, however, was not affected by heparin treatment. Thirty days after TIPS procedure prothrombin fragment F1+2 and endotoxemia returned to baseline values independently of the treatment given. CONCLUSION: This study shows that TIPS is associated with an increase of clotting activation which might contribute to acute thrombosis observed after this procedure.