Plasma von Willebrand factor as a predictor of survival in pulmonary arterial hypertension associated with congenital heart disease

Biomarkers have been identified for pulmonary arterial hypertension, but are less well defined for specific etiologies such as congenital heart disease-associated pulmonary arterial hypertension (CHDPAH). We measured plasma levels of eight microvascular dysfunction markers in CHDPAH, and tested for associations with survival. A cohort of 46 inoperable CHDPAH patients (age 15.0 to 60.2 years, median 33.5 years, female:male 29:17) was prospectively followed for 0.7 to 4.0 years (median 3.6 years). Plasma levels of von Willebrand factor antigen (VWF:Ag), tissue plasminogen activator (t-PA) and its inhibitor (PAI-1), P-selectin, reactive C-protein, tumor necrosis factor alpha, and interleukin-6 and -10 were measured at baseline, and at 30, 90, and 180 days in all subjects. Levels of six of the eight proteins were significantly increased in patients versus controls (13 to 106 percent increase, P < 0.003). Interleukin-10 level was 2.06 times normal (P = 0.0003; Th2 cytokine response). Increased levels of four proteins (t-PA, PAI-1, P-selectin, and interleukin-6) correlated with disease severity indices (P < 0.05). Seven patients died during follow-up. An average VWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was independently associated with a high risk of death (hazard ratio = 6.56, 95 percentCI = 1.46 to 29.4, P = 0.014). Thus, in CHDPAH, microvascular dysfunction appears to involve Th2 inflammatory response. Of the biomarkers studied, plasma vWF:Ag was independently associated with survival.

Rosuvastatin and vascular dysfunction markers in pulmonary arterial hypertension: a placebo-controlled study

We investigated whether chronic rosuvastatin administration could improve the abnormalities of the circulating levels of vascular dysfunction markers in pulmonary arterial hypertension (PAH). Sixty patients, aged 13 to 60 years, with idiopathic (N = 14) or congenital heart disease-associated PAH (N = 46) were equally but randomly assigned to rosuvastatin treatment (10 mg a day, orally) or placebo for 6 months in a blind fashion. Plasma levels of P-selectin, tissue-plasminogen activator and its inhibitor as well as von Willebrand factor antigen were measured by enzyme-linked immunoassay before and after 1, 3, and 6 months of treatment. Baseline levels of biomarkers were elevated (68, 16, 45 and 46 percent increase relative to controls, for P-selectin, von Willebrand factor antigen, tissue-plasminogen activator and its inhibitor, respectively; P < 0.001). P-selectin values at baseline, 1, 3, and 6 months were 39.9 ± 18.5, 37.6 ± 14.6, 34.8 ± 14.6, and 35.4 ± 13.9 ng/mL, respectively, for the rosuvastatin group and 45.7 ± 26.8, 48.0 ± 26.9, 48.1 ± 25.7, and 45.7 ± 25.6 ng/mL for the placebo group. The P-selectin level was lower in the rosuvastatin group compared with placebo throughout treatment (P = 0.037, general linear model). A trend was observed towards a decrease in tissue-plasminogen activator in the statin group (16 percent reduction, P = 0.094), with no significant changes in the other markers. Since P-selectin is crucial in inflammation and thrombosis, its reduction by rosuvastatin is potentially relevant in the pathophysiological scenario of PAH.

A mathematical framework for group analysis of von Willebrand factor multimeric composition following luminography

The objective of the present study was to establish a method for quantitative analysis of von Willebrand factor (vWF) multimeric composition using a mathematical framework based on curve fitting. Plasma vWF multimers from 15 healthy subjects and 13 patients with advanced pulmonary vascular disease were analyzed by Western immunoblotting followed by luminography. Quantitative analysis of luminographs was carried out by calculating the relative densities of low, intermediate and high molecular weight fractions using laser densitometry. For each densitometric peak (representing a given fraction of vWF multimers) a mean area value was obtained using data from all group subjects (patients and normal individuals) and plotted against the distance between the peak and IgM (950 kDa). Curves were constructed for each group using nonlinear fitting. Results indicated that highly accurate curves could be obtained for healthy controls and patients, with respective coefficients of determination (r²) of 0.9898 and 0.9778. Differences were observed between patients and normal subjects regarding curve shape, coefficients and the region of highest protein concentration. We conclude that the method provides accurate quantitative information on the composition of vWF multimers and may be useful for comparisons between groups and possibly treatments

Fator von Willebrand e disfunçäo endotelial pulmonar. Implicaçöes prognósticas / von Willebrand factor and pulmonary vascular endothelial cell dysfunction. Prognostic implications

OBJETIVO - Avaliar alteraçöes quantitativas e estruturais do fator von Willebrand (fvW) circulante em 40 pacientes com hipertensäo pulmonar pré-capilar e verificar possíveis implicaçöes prognósticas dos resultados iniciais, em um ano de seguimento. MÉTODOS - A atividade antigênica plasmática do fator von Willebrand (vWF:Ag) foi analisada por imunoeletroforese. A concentraçäo de multímeros de baixo peso molecular em relaçäo...

Decreased biological activity is related to abnormal multimeric structure of von Willebrand factor in pulmonary hypertension

We evaluated the correlation between decreased biological activity and abnormalities in the multimeric structure of plasma von Willebrand factor (vWF) in 27 pulmonary hypertensive patients (median age, 21 years). The biological activity of vWF was measured by the ristocetin cofactor assay and its multimeric structure was assessed by Western immunoblotting after SDS-agarose gel electrophoresis. In spite of high antigenic activity of vWF in plasma (139 ñ 65 vs 91 ñ 27 per cent in controls, P=0.003), the biological activity expressed as a percent of the control value was decreased in pulmonary hypertensive patients (60-88 per cent activity, 95 per cent CI for the mean). High molecular weight multimers (biologically active forms) were absent in patients and there was a significant increase in the concentration of low molecular weight polymers in comparison with normals (56 ñ 12 and 35 ñ 12 per cent of total multimer density, respectively, P<0.001). Multimeric abnormalities were positively correlated with plasma vWF levels (r=0.51, P=0.0007) and negatively correlated with vWF biological activity (r=-0.54, P=0.004). Thus, decreased biological function is related to abnormalities in the multimeric structure of vWF, possibility reflecting extensive endothelial dysfunction in pulmonary hypertension.

Plasma anticoagulant system in patients with pulmonary hypertension

Adults with pulmonary hypertension and polycythemia (N=22) have low levels of plasma antithrombin III (84 ñ 18 vs 98 ñ 13½ for controls, N=35, P<0.005) and protein C (66ñ21 vs 125 ñ 30%, N 8, P<0.0002 but normal levels of total protein S. Data are reported as means ñ SD and percent normal values obtained for pooled plasma from normal healthy adults. Children with the same disorder (N = 6) also had low protein C levels (66 ñ 16 vs 85 ñ 5½, P < 0.025). Total protein S was normal for children, but free protein S was decreased (66 ñ 13 vs 91 ñ 23,, P < 0.02). Since the levels observed in these patients are above those reported for congenital deficiencies, the reduction in plasma levels of anticoagulant proteins may be the result of cronic intravascular coagulation. Furthermore, normal levels of plasminogen and fibrin degradation products suggested a localized disorder or an acquired decrease in fibronolytic activity

Platelet regeneration time: a statistical approach

The determination of platelet regeneration half-time (PRT t1/2) by measuring malondialdehyde after intake of acetylsalicylic acid is a simple nonisotopic method for the estimation of platelet survival. There is no available information concerning the populational distribution of PRT t1/2. Consequently, there is controversy about the utilization of parametric or nonparametric statistical tests in studies of PRT. In the present study, we demonstrate the closeness of the fit of log PRT t1/2 to the normal (Gaussian) distribution