Hyperhomocysteinaemia in renal allograft recipients: could methylenetetrahydrofolate reductase gene polymorphism be a determinant risk factor for chronic allograft dysfunction?

The elevated plasma homocysteine could adversely influence long-term renal graft survival by promoting vascular sclerosis in the kidney allograft. This could be mediated through endothelial dysfunction. A polymorphism C677T in the gene coding for the enzyme methylenetetrahydrofolate reductase [MTHFR] was identified. The aim of the present work was to study the influence of the C677T MTHFR gene polymorphism on total plasma homocysteine and folate levels in renal graft recipients, and its impact on chronic graft dysfunction and the associated endothelial dysfunction. Thirty two stable renal allograft recipients were included in this study [group I] and compared with age and sex matched thirty control subjects [group II]. Plasma homocysteine level, plasma folic acid level, plasma van Willebrand factor [vWF] activity together with endothelial dependent and independent brachial artery vascular responses were done for all subjects. MTHFR genotype was determined by PCR in all renal recipients who were further classified accordingly into 3 subgroups: [group Ia] with homozygous TT type, [group Ib] with heterozygous CT type, and [group Ic] is wild CC type. Renal allograft recipients showed significant higher level of homocysteine as compared to control group [44.42 +/- 32.08 vs 11.62 +/- 2.57 respectively, p<0.001]. There was significant endothelial dysfunction in the transplant group as evidenced by the higher vWF [119.71 +/- 17.71 vs 67.60 +/- 28.65 p<0.001] and poorer endothelial dependent dilatation [EDD] of the brachial artery [7.84 +/- 1.08 vs 12.68 +/- 0.96 p<0.001] as compared to the control group. There was significant negative correlation between plasma homocysteine level and creatinine clearance [r=-0.55, p=0.001], suggesting the deleterious effect of hyperhomocysteinaemia on graft function. The homozygous subgroup [gpIa] showed significant higher level of homocysteine, vWF, lower folic acid, creatinine clearance and EDD as compared to the other two subgroups [gp Ib and Ic]. Our study identified that the presence of hyperhomocysteinemia in combination with unfavorable MTHFR genotypes contributes to an increased risk for development of chronic allograft dysfunction

Microalbuminuria and endothelial dysfunction in hypertensive patients with and without cerebral lacunar infarctions

This study included 14 nondiabetic persons with untreated essential hypertension and cerebral lacunar infarctions detected by MRI or CT brain scan, 12 age and sex matched untreated nondiabetic hypertensive patients without infarction and 11 normal controls. Urinary albumin excretion [UAE] was measured photometrically and von Willebrand factor [vWF] as a known marker of endothelial dysfunction was estimated by a platelet aggregation method. UAE was found to be significantly higher in hypertensives with lacunar infarctions compared with those without and to normal control. VWF concentrations were found to be significantly higher in patients with lacunar infarctions compared with those without and with the normal control, but there was no significant difference between its level in hypertensives without lacunae and the normal controls. There was a significant positive linear correlation between vWF and UAE values in hypertensive patients with lacunar infarctions. Increased systolic blood pressure and low HDL correlated with both UAE and vWF in patients with lacunar infarctions

Von wilebrand factor in acute myocardial infarction

To determine the sensitivity of von Willebrand factor [vWF] and fibrinogen as diagnostic predictors of vascular injury in acute myocardial infarction [MI], the changes in plasma level of vWF and fibrinogen were assessed in 15 patients with acute MI, 15 patients with unstable angina and 10 control subjects with no subjective or objective evidence of ischemia. The samples were obtained immediately on admission from all groups. In patients with acute MI, the samples were drawn at 24 hours and 5 days later. The samples were analyzed for serum cardiac enzymes, vWF and fibrinogen. Plasma concentrations of vWF antigen were measured by enzyme linked immunosorbent assay [ELISA] method and by coagulation method for fibrinogen level. Compared with the control subjects, patients with acute MI and unstable angina had significantly higher levels of plasma vWF on admission. Twenty four hours and 5 days later, the plasma levels of vWF increased significantly from 203.6 +/- 17.7 and 252.6 +/- 2.6, respectively, compared with that on admission [104.1 +/- 23.8]. On the other hand, fibrinogen levels were significantly higher in patients with unstable angina compared with the control subjects, but insignificantly higher than that in patients with acute MI

Correlation between extent of tumor vascularization, prognosis and hematogenous metastases in gastric carcinoma using vascular endothelial growth factor [VEGF] and Von-Willebrand factor

Angiogenesis has a crucial importance for tumor growth and development of metastasis. This study aimed to evaluate angiogenesis. Microvessel density [MVD] was counted by staining endothelial cells immunohistochemically using anti von Willebrand vWF [factor VIII] antibody as well as vascular endothelial growth factor [VEGF], a known endothelial proliferative and mitogenic marker. Thirty prospective cases [24 cases of adenocarcinoma and 6 of diffuse infiltrating tumors] were enrolled in this study. Then, four cases were excluded from the study because they had inoperable tumors. Thus, a total of 26 patients was studied histologically, immunohistochemically and followed up for a period ranging from 6-30 months [median 12 months]. The immunohistochemical results of these biomarkers were correlated with standard prognostic factors [tumor grade, stage and lymph node metastasis] as well as overall survival period. It was found that MVD was significantly increased in deep advanced tumors and in the presence of nodal metastasis. However, VEGF positivity was demonstrated in only 46% of the cases and was not correlated with the clinicopathologic parameters. The MVD for cases that developed hematogenous metastasis was significantly higher than those having non metastatic tumors. Also, MVD was correlated with a relatively higher survival rates in favor of the hypovascular group

Assessment of the role of hypephomccysteinemia and its metabolic consequences in the vascular access thrombosis among hemodialysis patients

The aim of this work was, to determine whether hyperhomocysteinemia and its metabolic consequences are associated with vascular access thrombosis in patients with end stage renal disease [ESRD], undergoing chronic hemodiahysis [HD]. This study included 3 groups. Group I: 15 ESRD patients on regular HD, with history of more than one episode of vascular access thrombosis. Group II: 15 ESRD patients on regular HD, with no episodes of vascular access thrombosis. Group III: 10 healthy, age and sex matched individuels as a control group. Plasma total homocysfeine [tHcy] and Von Willebrand Factor [vWF] were estimated by ELISA. Determination of plasma folate was done by Radioimmunoassay [RIA]. Plasma glutathione peroxidase activity was estimated by modified Paglia and Valentine method. Plasma methionine and cysteine levels were estimated by amino acid autoanalyser. plasma Hcy levels of both HD groups [GI and GII] were significantly higher than control groups [GIII] [F value = 44,487, P<0.0001], while no significant difference was found between GI and GII. Plasma folic acid levels of both patients' groups were significantly higher than control group [F value = 29.063, P<0.0001], while there was no significant difference between its level in GI and GII. Plasma vWF of HD patients with vascular access thrombosis [GI] was significantly higher than that of both GII and GIII and that of GII was significantly higher than GIII [F value = 62.010, P<0.0001]. Plasma glutathione peroxidase activity of both HD groups [GI and GII] was significantly lower than the control group [GIII] [F value = 69.446, P<0.0001], also its activity in patients with vascular access thrombosis [GI] was significantly lower than that of patients without vascular access thrombosis [GII]. Plasma cysteine and methionine levels of both HD groups were not significantly different from control group, also there was no significant difference in their levels between GI and GII. Plasma Hcy levels showed no significant correlation with number of vascular access thrombosis, whereas it showed a significant positive correlation with plasma vWF [r = 0.474, P<0.01] and negative correlation with plasma glutathione peroxidase activity [r = 0.643, P<0.0001]. From the previous study we concluded that: Hyperhomocyteinemia is not a direct cause of vascular access thrombosis. It is linked with increased plasma vWF levels. Endlothelial injury induced by hyperhomocysteinemia may be the cause. The lower levels of plasma glutathione peroxidase activity reflect increased oxidative stress induced by hyperhomocyteinemia in hemodialysis patients

Platelet aggregation and von willebrand factor in children with insulin dependent diabetes mellitus

Microvascular complications of diabetes mellitus represent the most serious complications that burden normal life in insulin dependent diabetic patients. It has been speculated that platelet activation and von Willebrand factor [vWF] activity might contribute to the evolution of microvascular complications in patients with insulin dependent diabetes mellitus [IDDM]. In this study, platelet aggregation [in response to ADP and ristocetin] and vWF activity were measured in 20 children with IDDM who were clinically free from demonstrable microvascular complications, and in 10 normal healthy children of matched age and sex served as control group. The results showed an abnormal platelet behavior in diabetic children that was characterized by irreversible aggregation with low dose of ADP and significant increase in peak wave length of platelet aggregation with both ADP and ristocetin. Also the activity of vWF which is a marker of endothelial cell function was significantly higher in diabetic children compared to control group. The studied parameters, were compared with the state of metabolic control, namely glycemic control by measurement of glycated haemoglobin [Hb A1c] and the lipidemic state assessed by serum total cholesterol levels. Platelet aggregation was positively correlated with the serum cholesterol level while vWF was positively correlated with the level of glycated haemoglobin. Meanwhile vWF activity was positively correlated with platelet aggregation. To conclude; the results of this study suggest that diabetic children who are clinically free from detectable microvascular complications might be at the onset of preclinical microangiopathy manifesting itself by the enhanced platelet aggregation and endothelial cell dysfunction [high vWF activity]. Both the glycemic and lipidemic states seem to affect the enhanced platelet activation and increased vWF

role of von-wellbrand's factor; fibronectin and lipid profile as risk factors for vascular damage in rheumatoid arthritis and systemic sclerosis

This study was designed to determine the roles of Von-Willbrand's factor, fibronectin and lipid profile as risk factors in etiopathogensis of vascular lesions in 20 rheumatoid disease patients [RD] diagnosed according to American Rheumatism Association Criteria and 20 Systemic Sclerosis patients [SSc] diagnosed according to the preliminary criteria for SSc. 20 healthy subjects of matched age and sex were included as control group. Variable degrees of vascular lesions were detected: Raynouds phenomenon [RD 30%, SSc 50%] cutaneous telangiectasia and digital ulcers [RD 5%, SSc 40%], peripheral vascular insufficiency via Doppler study [RD 5%, SSc 40%], clinically evident systemic hypertension [SSc 15%], pulmonary vascular disease via Echo-Doppler study [RD 5%, SSc 20%], Coronary heart disease via E.C.G and Echo-Doppler study [20% in RD, 15% in SSc] and clinically evident cerebrovascular strokes [RD 10% SSc 10%]. The mean plasma levels of Von-Willebrand's factor and fibronectin were significantly higher in RD and SSc patients than in controls and the highest levels were observed in patients with vascular manifestations particularly with SSc., suggesting the presence of endothelial dysfunction and were considered as non invasive markers of vascular damage which are more prominant in SSc than in RD. The total serum lipids, Triglycerides, cholesterol, LDL-cholesterol, free fatty acids and Apoprotein B-were, significantly increased while HDL-cholesterol and apoprotein A, were significantly decreased, suggesting the presence of atherogenic dyslipidemic pattern in the etiopathogenesis of vascular manifestations in RD and SSc. The higher levels which observed in RD patients with vascular manifestations are most probably due to patients inactivity resulting from articular lesions or due to steroid therapy induced dyslipedemia. Circulating levels of endothelial cell products such as VWF and fibronectin may reflect the role of the immune mechanism in the pathogenesis of RD and SSc vascular disease and assist the clinician in monitoring response to therapy. Furthermore, monitoring of VWF and fibronectin as parameters of endothelial cell injury may help to define the vascular disease in an early and more measuringful fashion

Von Willebrand factor: a biomarker of endothelial cell damage in dehydrated and malnourished children

The level of von Willebrand factor [vWF] as a marker of endothelial cell injury was evaluated in 73 children with age ranged from 3 to 30 months. Twenty-three cases suffered from dehydration, nineteen from marasmus, twelve from Kwashiorkor [KWO] and nineteen healthy children were included as controls. In both dehydrated and malnourished groups, the level of vWF was highly significantly elevated than the control group. A strong negative correlation was found between vWF and each of hemoglobin level, hematocrit, red blood cell count as well as several anthropometric Z scores [HAZ, WAZ and BMI]. The prothrombin concentration also correlated significantly and negatively with vWF level. In the dehydration group, vWF level correlated strongly and positively with the score of clinical severity. This work demonstrated that the integrity of the endothelium is likely to be affected in dehydration and malnutrition where pathologic unfavorable conditions are likely to exist. The measurement of vWF levels in such conditions proved to be benefit in accurate assessment as well as prognosis

Vaso-active mediators and doppler indices in maternal and fetal vessels in pre-eclampsia

Pre-eclampsia is associated with increased vascular reactivity and vasoconstriction. Forty six women whose pregnancy were complicated with pre-eclampsia and twenty six normotensive pregnant women all at the same duration of pregnancy were studied. Pre-eclampsia occurred in the 2nd trimester only in two patients, in the sometime it occurred in 28 patients before the 37th weeks and 16 after the 37th weeks. Only eight patients were with moderate hypertension, while 38 patients were with severe disease. Blood flow velocity waveforms in both right and left uterine arteries, fetal umbilical artery and fetal descending aorta was done for both patients and controls. Serum levels of endothelin-I [ET1], prostaglandin E2 [PGE2], nitric oxide [NO], Von Willebrand factor [vWF] and angiotensin converting enzyme activities [ACE], were determined for both patients and controls. Serum levels of ET-1, ACE and vWF were higher, while serum levels of NO and PGE2 were lower to statistically significant levels [p<0.001] in pre-eclamptic women in all instances. Also, all Doppler indices were significantly higher in patients with pre-eclampsia than in normotensive women [p<0.001]. There was strong positive correlation between Doppler indices and serum levels of ET-1, ACE and vWP and strong negative correlation with NO and PGE2 in both patients with pre-eclampsia and in normotensive women [r<0.05]. These changes confirm the presence of highlight vascular reactivity and endothelial damage in cases of pre-eclampsia. The resulting endothelial damage and dysfunction may underlay the pathologic features of this disorder