Tissue factor pathway inhibitor levels in patients with homocystinuria

Thrombotic events are a well-recognized complication of homocystinuria, How ever, the mechanisms involved in the atherogenic and thrombotic effects of homocyst(e)ine remain incompletely understood. The objective of this study was to determine the role of endothelial cell activation/damage as indicate d by levels of thrombomodulin, tissue factor and tissue factor pathway inhi bitor, and factor VII activity in patients with homocystinuria, Six patient s with homocystinuria, nonresponsive to pyridoxine, treated only with trime thylglycine (betaine) were injected with a bolus of 20 IU/kg body weight of unfractionated commercial heparin to induce the release of tissue factor p athway inhibitor from the vascular endothelium. Tissue factor, thrombomodul in, and factor VII activity were measured by enzyme-linked immunosorbent as say and clotting assay before heparin administration. Tissue factor pathway inhibitor antigen and activity were measured before and 5 minutes after th e bolus of heparin, Levels of homocyst(e)ine were elevated (patients: 144.2 +/-19.2 mu mol/L; controls: 10.2+/-0.9 mu mol/L); however, levels of thromb omodulin, tissue factor, and tissue factor pathway inhibitor antigen were n ot statistically different from the control g-e group. In contrast: tissue factor pathway inhibitor activity showed a significantly increased level (p atients: 2.09+/-0.34 U/L; controls: 1.14+/-0.20 U/L; p<0.05) that was corre lated with homocyst(e)ine. Factor VII activity was significantly decreased (patients: 64.7+/-5.1%; controls: 91.4+/-4.7%; p<0.05) and inversely correl ated with homocyst(e)ine. After heparin the patients released higher amount s of tissue factor pathway inhibitor antigen and activity compared with the control group; however, the difference was not statistically significant. Although not treated with antithrombotic drugs, none of the patients had an y thromboembolic complications after starting betaine. In addition to betai ne treatment, the enhanced factor pathway inhibitor antigen activity observ ed in this small series of patients suggests that factor pathway inhibitor antigen may play an additional, as yet unexplained, role in this genetic di sorder. (C) 2000 Elsevier Science Ltd. All rights reserved.