Nitric Oxide and Von Willebrand Factor Levels as Markers of Endothelial Dysfunction in Liver Cirrhosis

Introduction: A number of investigators have shown that endothelial dysfunction in liver cirrhosis can be indicated by increased levels of nitric oxide (NO) and von Willebrand factor (vWF). The cause of this increase is still unclear. It is believe to be correlated with hyperdinamic circulation and endotoxemia, which are common in liver cirrhosis. The Aim of This Study: To compare the levels of NO and vWF in liver cirrhosis patients with those in healthy control subjects, and to investigate whether there is a correlation between levels of NO and vWF with the severity of the disease according to the Child Pugh Criteria Material and Method: This study was conducted from February until June 2001 in 35 liver cirrhosis patients at Dr. Pirngadi and H. Adam Malik Hospital and some private hospitals in Medan. The mean age of patients with liver cirrhosis was 54 + 12.26 years, the youngest being 31 years and the oldest 75 years, and 20 healthy controls while the mean age of the control subject was 55.20 + 13.04 years, the youngest being 31 years and the oldest 76 years. Based on Child Pugh criteria, 9 were classified as Child Pugh class A, 13 in class B, 13 in class C. The criteria for liver cirrhosis were based on clinical examination, laboratory findings and liver ultrasound examination. Cirrhotic patients with hypercolestrolemia, hypertension, heart failure, myocardial infraction, renal failure diabetes, COPD were those on drugs, such as antibiotics and branchodilators were excluded from the study. Result: The mean level of NO in patients with liver cirrhosis was 6.2600 + 4.4456 mM, while the mean NO level in control subjects was 3.2325 + 3.2355 mM, p<0.05. The mean level of NO in Child Pugh class A patients was 6.6889 + 3.9757mM, compared to control p<0.05; in Child Pugh class B the mean level was 4.8308 + 2.4642 mM compared to control p>0.05. There was a significant increase in the level of NO associated with the severity of liver cirrhosis. The mean level of vWF in patients with liver cirrhosis was 399.514 + 175.313% while the mean vWF level in control subjects was 139.100 + 51.144%, p<0.05. The mean level of vWF in Child Pugh class A patients was 231.778 ± 43.8576%, compared to control p<0.05; in Child Pugh class B was 365.846 + 110.034%, compared to control p<0.05, in Child Pugh class C was 549.308 + 164.483%, compared to control p<0.05. There was significant increase in the level of vWF correlated with severity of liver cirrhosis. Conclusion: The level of NO was significant higher in liver cirrhosis patients compared to control subjects, but there was no correlation between the increase in the level of NO with the severity of the disease. The levels of vWF was significantly higher in liver cirrhosis patients compared to control, and there was a correlation between increased levels of vWF and the severity of the disease

von Willebrand factor and early diabetic retinopathy: no evidence for a relationship in patients with Type 1 (insulin-dependent) diabetes mellitus and normal urinary albumin excretion

High plasma levels of von Willebrand factor, an indicator of endothelial cell dysfunction, have been reported in both diabetic retinopathy and nephropathy. It is unclear, however, whether von Willebrand factor is related to diabetic retinopathy in the absence of diabetic nephropathy. The relationship between retinal status and plasma von Willebrand factor concentration was investigated in a cohort of 17 patients with Type 1 (insulin-dependent) diabetes mellitus who were followed-up for a median of 42 months. The patients were examined three times. They were selected for having had normal urinary albumin excretion and no evidence of retinopathy (on fundoscopy) at the first and second examination. They were then divided into two groups, according to absence (Group A;n=9) or presence (Group B;n=8) of retinopathy on fundoscopy or fluorescein angiography at the third examination. Urinary albumin excretion remained normal in all patients. Plasma von Willebrand factor levels were similar in both groups: (median) 128 vs 123 %, 164 vs 132% and 159 vs 130 % (first, second and third examination, respectively). Median changes in plasma von Willebrand factor were also similar: +7 vs +9 % and +5 vs +1 % (first-second and second-third examination). Patients in whom the plasma von Willebrand factor concentration increased had higher systolic blood pressure at the third examination (150±30 vs 130±12 mmHg,p=0.02) when compared to those in whom plasma von Willebrand factor did not increase, but were of similar age and had similar diabetes duration, retinal status, diastolic blood pressure, glycated haemoglobin and serum cholesterol concentration. These data do not support the hypothesis that increases in plasma von Willebrand factor concentration reflect retinal endothelial injury in Type 1 diabetic patients with normal urinary albumin excretion. In these patients, high or increasing plasma von Willebrand factor levels may be related to systolic blood pressure

Some aspects of pathogenesis of erosive-ulcerous gastric lesions in liver cirrhosis patients

Von Willebrand factor, tumor necrosis factor-α levels and portal bloodstream were examined in 47 patients with liver cirrhosis and 8 apparently healthy persons. The increase of von Willebrand factor and tumor necrosis factor-α levels were found to lead to the development of erosive-ulcerative lesions of gastric mucosa. The abnormalities of portal resistance, von Willebrand factor and TNF-α are interrelated data which play a certain role in occurrence of erosive-ulcerative lesions of gastric mucosa in patients with liver cirrhosis

Increased plasma von Willebrand factor antigen levels but normal von Willebrand factor cleaving protease (ADAMTS13) activity in preeclampsia.

The activity of ADAMTS13, the von Willebrand factor (VWF) cleaving protease is low in several conditions, including HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome. As HELLP syndrome develops in most cases on the basis of preeclampsia, our aim was to determine whether plasma ADAMTS13 activity is decreased in preeclampsia. Sixty-seven preeclamptic patients, 70 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Plasma ADAMTS13 activity was determined with the FRETS-VWF73 assay, while VWF antigen (VWF:Ag) levels with an enzyme-linked immunosorbent assay. The multimeric pattern of VWF was analyzed by SDS-agarose gel electrophoresis. There was no significant difference in plasma ADAMTS13 activity between the preeclamptic and the healthy pregnant and non-pregnant groups (median [25-75 percentile]: 98.8 [76.5-112.8] %, 96.3 [85.6-116.2] % and 91.6 [78.5-104.4] %, respectively; p > 0.05). However, plasma VWF:Ag levels were significantly higher in preeclamptic patients than in healthy pregnant and non-pregnant women (187.1 [145.6-243.1] % versus 129.3 [105.1-182.8] % and 70.0 [60.2-87.3] %, respectively; p < 0.001). The multimeric pattern of VWF was normal in each group. Primiparas had lower plasma ADAMTS13 activity than multi-paras (92.6 [75.8-110.6] % versus 104.2 [92.1-120.8] %; p = 0.011). No other relationship was found between clinical characteristics, laboratory parameters and plasma ADAMTS13 activity in either study group. In conclusion, plasma ADAMTS13 activity is normal in preeclampsia despite the increased VWF:Ag levels. However, further studies are needed to determine whether a decrease in plasma ADAMTS13 activity could predispose preeclamptic patients to develop HELLP syndrome

Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemia: Relationship with platelet count

We present a 4-year follow-up of a 42-year-old patient with primary thrombocythemia whose clinical course was complicated by two major mucocutaneous bleeding episodes. On both occasions an acquired functional von Willebrand factor deficiency was demonstrated. In contrast to what is reported in the literature, an inverse relationship between platelet number and plasma high-molecular-weight multimers of von Willebrand factor was established

Weibel-Palade body formation and exocytosis in von Willebrand disease

The studies presented in this thesis explored several pathogenic mechanisms underlying von Willebrand disease that is characterized by a quantitative or functional deficiency of von Willebrand factor, in particular with respect to intracellular storage in Weibel-Palade body and regulated secretion of von Willebrand factor. By using molecular biology, confocal and electron microscopic techniques, storage and secretion of von Willebrand factor were analyzed for von Willebrand disease variants identified in the patients. These studies advanced our understanding of von Willebrand disease at the molecular and cellular levels. HEK293 cells and endothelial cells derived from patients__ peripheral blood were established as two useful model-systems for examining von Willebrand factor structure-function relationships in the context of von Willebrand disease. Using these model-systems we have demonstrated that von Willebrand factor mutations may impair its storage and secretion and thus lead to a quantitative deficiency of this factor in the patients. Furthermore, we demonstrated that alteration in the structure of von Willebrand factor, by natural mutations that occur in von Willebrand disease patients, modulates von Willebrand factor string formation and function. We propose that alteration in von Willebrand factor string formation and function may be another new mechanism that contributes to the bleeding tendency in von Willebrand disease.Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, LUMCUBL - phd migration 201

Levels of von Willebrand factor antigen and von Willebrand factor cleaving protease (ADAMTS13) activity predict clinical events in chronic heart failure.

Decreased activity of ADAMTS13, the von Willebrand factor (VWF) cleaving protease, was recently reported in cardiovascular diseases and in hepatic failure. Chronic heart failure (CHF) is characterised by abnormalities of left ventricular function accompanied by the failure of the liver and dysregulation of endothelial activation. Therefore, the aim of our study was to measure ADAMTS13 activity in CHF, and determine the prognostic value of VWF and ADAMTS13 on major clinical events in CHF. ADAMTS13 activity (measured by FRETS-VWF73 substrate) was decreased in CHF (n = 152, left ventricular ejection fraction <45%), and it correlated negatively with B-type natriuretic peptide (BNP) NYHA (New York Heart Association) classes, markers of synthetic capacity of the liver and endothelial dysfunction (all p < 0.005). Both, high VWF:Ag levels (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.189-1.943), and low ADAMTS13/VWF:Ag ratios (HR 0.70, 95% CI 0.58-0.84) independently and significantly predicted short-term (1 year follow-up) clinical adverse events in heart failure (HF). Decreased activity of ADAMTS13 with concomitant high VWF:Ag levels is a significant independent predictor of clinical events in CHF. The levels of the two molecules may integrate the impaired synthetic capacity of the liver and the disturbed endothelial regulation and can therefore be a useful tool to predict clinical events in CHF