No abstract

In pulmonary hypertension (PH), defective plasma von Willebrand factor (vWF) lacking the larger multimers with increased concentration of low-molecular-weight fractions (LMW) has been reported, although the mechanisms involved are not completely known. Altered platelet behavior may be involved in this alteration; this hypothesis was investigated in 10 patients with PH associated with chronic hypoxemia and erythrocytosis (age 13 to 51 years, mean pulmonary artery pressure 38 to 98 mmHg). The possible influence of the hematocrit (Hct) and decreased oxygen saturation (SpO2) on vWF abnormalities was examined. Patients were evaluated before and after therapeutic hemodilution. vWF alterations were quantified using the ratio of LMW/total multimers (densitometric analysis of luminographs after Western blotting). Platelet count and activation state (plasma levels of beta-thromboglobulin, enzyme-linked immunosorbent assay), the Hct and SpO2 were also assessed before and after hemodilution. Platelet activation and consumption were suggested by increased plasma beta-thromboglobulin (p=0.0444) with decreased platelet count (p<0.001). Altered vWF LMW/total ratio correlated significantly with decreased platelet count (p=0.0066) and low SpO2 (p=0.0088). The effects of both variables were independent and additive (p=0.0031, multiple regression). Hemodilution was followed by an increase in platelet count (p=0.0013) associated with improvement of LMW/total ratio (p=0.0079). Residual vWF alterations were associated with persistent hypoxemia and residual platelet activation (plasma beta-thromboglobulin still increased). These data suggest a common mechanism for platelet and vWF abnormalities in these chronically hypoxic PH patients. Hypoxia itself may play a role, possibly inducing endothelial release of unprocessed (LMW) vWF molecules.

Endothelial dysfunction has been reported in hypoxaemic patients with the Eisenmenger syndrome, but a direct correlation between levels of endothelial markers and the severity of hypoxaemia has not been explored. With this in mind, we compared the levels in the plasma of tissue-type plasminogen activator, thrombomodulin, and von Willebrand factor in 25 patients with the Eisenmenger syndrome. They had a median age of 31 years, and were divided into 2 groups according to their recent clinical history. Thus, 18 patients were stable, being in functional class II or III, seen as outpatients, and having peripheral saturations of oxygen of 89 plus or minus 5 percent. In contrast, 7 patients were unstable, showing episodes of symptoms placing them in functional class IV, requiring care in hospital, and manifesting saturations of oxygen of 77 plus or minus 5 percent. We were able to follow 12 patients, 8 who were stable and 4 unstable, for 24 months. At baseline, levels of von Willebrand factor were higher in the unstable patients when compared to those who were stable, at 142 plus or minus 29 and 110 plus or minus 25 units per decilitre, respectively (p equal to 0.013). This correlated positively with oxygen desaturation (p less than 0.020). The structural abnormalities also correlated positively with the magnitude of hypoxaemia (p less than 0.020). Levels remained higher in the unstable patients throughout the period of follow-up (p equal to 0.006). Tissue-type plasminogen activator was also increased, at 14.3 plus or minus 8.4 versus 6.5 plus or minus 2.7 nanograms per millilitre in controls (p less than 0.001), whereas thrombomodulin was decreased, with values of 14.4 versus 34.6 nanograms per millilitre in controls (p for median values of less than 0.001). There was no correlation with saturations of oxygen. We conclude that measurement of von Willebrand factor, as compared with tissue-type plasminogen activator and thrombomodulin, will prove a better marker of endothelial response to hypoxaemia in patients with the Eisenmenger syndrome.