Long-term Behavior of Endothelial and Coagulation Markers in Eisenmenger Syndrome

Abstract

The long-term behavior of endothelial markers was studied in patients with Eisenmenger syndrome who were subjected to conventional therapy (no vasodilators) and observed for 18 months. Biochemical markers were analyzed comparatively in patients with class II or III symptoms (group 1, n=10) and patients with class IV symptoms (group 2, n=7). Plasma von Willebrand factor antigen (vWF: Ag), thrombomodulin, tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and D-dimer were determined by immunoenzymatic assay at baseline, and at 6, 12, and 18 months. At baseline, the main clinical difference between groups was a decreased peripheral oxygen saturation in group 2 versus group 1 (77±5% and 86±4%, respectively, p=0.001). Basal vWF: Ag and t-PA were increased and thrombomodulin was decreased in both groups in comparison with controls (p<0.0001), while D-dimer was increased in group 2 only (p=0.0003). In response to treatment, there was a decrease in vWF: Ag in both groups (19% and 23%, respectively in groups 1 and 2, at 18 months vs. baseline, p<0.0001) and t-PA in group 1 (38% vs. baseline, p=0.0485). Plasma vWF: Ag tended to be higher in group 2 in comparison with group 1 during the whole follow-up. Levels of PAI-1 greater than 38.4 ng/mL (upper 90% limit for normals) and D-dimer greater than 500 ng/mL were detected in individual patients (both groups) during the follow-up period. Thrombomodulin remained decreased in both groups. Thus, severity of symptoms in the Eisenmenger syndrome appears to correlate with low oxygen saturation and higher vWF: Ag levels. Improvement of endothelial dysfunction may occur in response to treatment, although increased risk for thrombosis persists, in view of residual abnormalities.

Keywords

Pulmonary hypertension Eisenmenger syndrome Endothelial dysfunction Endothelial markers Hypoxia Erythrocytosis

References

Vongpatanasin W , Brickner E , Hillis LD , et al. The Eisenmenger syndrome in adults. Ann Intern Med 1998;128:745-745.

Smith KJ , Bleyer AJ , Little WC , et al. The cardiovascular effects of erythropoietin. Cardiovasc Res 2003;59:538-538.

Perloff JK , Hart EM , Greaves SM , et al. Proximal pulmonary arterial and intrapulmonary radiologic features of Eisenmenger syndrome and primary pulmonary hypertension. Am J Cardiol 2003;92:182-182.

Silversides CK , Granton JT , Konen E , et al. Pulmonary thrombosis in adults with Eisenmenger syndrome. J Am Coll Cardiol 2003;42:1982-1982.

Caramurú LH , Maeda NY , Bydlowski SP , et al. Age-dependent likelihood of in situ thrombosis in secondary pulmonary hypertension. Clin Appl Thromb Hemost 2004; 10:217-217.

Eisenberg PR , Lucore C , Kaufman L , et al. Fibrinopeptide. A level indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. Circulation 1990;82:841-841.

Huber K , Beckmann R , Frank H , et al. Fibrinogen, t-PA, and PAI-1 plasma levels in patients with pulmonary hypertension. Am J Respir Crit Care Med 1994;150:929-929.

Altman R , Scazziota A , Rouvier J , et al. Coagulation and fibrinolytic parameters in patients with pulmonary hypertension. Clin Cardiol 1996;19:549-549.

Chaouat A , Weitzenblum E , Higenbottam T. The role of thrombosis in severe pulmonary hypertension. Eur Respir J 1996;9:356-356.

10.

Welsh CH , Hassell KL , Badesch DB , et al. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996;110:710-710.

11.

Hassell KL. Altered hemostasis in pulmonary hypertension. Blood Coagul Fibrinolysis 1998;9:10-10.

12.

Farber HW , Loscalzo J. Prothrombotic mechanism in primary pulmonary hypertension. J Lab Clin Med 1999; 134:561-561.

13.

Veyssier-Belot C , Cacoub P. Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension. Cardiovasc Res 1999;44:274-274.

14.

Cella G , Bellotto F , Tona F , et al. Plasma markers of endothelial dysfunction in pulmonary hypertension. Chest 2001;120:1226-1226.

15.

Shitrit D , Bendayan D , Baar-Gil-Shitrit A , et al. Significance of a plasma D-dimer test in patients with primary pulmonary hypertension. Chest 2002;122:1674-1674.

16.

Cacoub P , Karmochkine M , Dorent R , et al. Plasma levels of thrombomodulin in pulmonary hypertension. Am J Med 1996;101:160-160.

17.

Friedman R , Mears JG , Barst RJ. Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension. Circulation 1997;96:2782-2782.

18.

Gonçalves RC , Buschpigell CA , Lopes AA. Circulating blood volumes in pulmonary hypertension associated with erythrocytosis—the effects of therapeutic hemodilution. Cardiol Young 2003;13:544-544.

19.

Pepper MS. Extracellular proteolysis and angiogenesis. Thromb Haemost 2001;86:346-346.

20.

Ruggeri ZM. Structure and biosynthesis of von Willebrand factor. In: Ruggeri ZM , ed. von Willebrand Factor and the Mechanism of Platelet Function. Berlin: Springer, 1998:33-33.

21.

Pinsky DJ , Naka Y , Liao H , et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies: A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996;97:493-493.

22.

Pepper MS , Rosnoblet C , Di Sanza C , et al. Synergistic induction of tissue-type plasminogen activator (tPA) by vascular endothelial growth factor and basic fibroblast growth factor and localization of t-PA to Weibel-Palade bodies in bovine microvascular endothelial cells. Thromb Haemost 2001;86:702-702.

23.

Michiels C , Arnould T , Remacle J. Endothelial cell responses to hypoxia: Initiation of a cascade of cellular interactions. Biochim Biophys Acta 2000;1497:1-1.

24.

Wu KK , Matijevic-Aleksic N. Thrombomodulin: A linker of coagulation and fibrinolysis and predictor of risk of arterial thrombosis. Ann Med 2000;32:73-73.

25.

Takahashi H , Ito S , Hanano M , et al. Circulating thrombomodulin as a novel endothelial cell marker: Comparison of its behavior with von Willebrand factor and tissue-type plasminogen activator. Am J Hematol 1992;41:32-32.

26.

Salomaa V , Matei C , Aleksic N , et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the atherosclerosis risk in communities (ARIC)) study: A case-cohort study. Lancet 1999;353:1729-1729.

27.

Ogawa S , Gerlach H , Esposito C , et al. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. J Clin Invest 1990;85:1090-1090.

28.

Uchiyama T , Kurabayashi M , Ohyama Y , et al. Hypoxia induces transcription of the plasminogen activator inhibitor-1 gene through genistein-sensitive tyrosine kinase pathways in vascular endothelial cells. Arterioscler Thromb Vasc Biol 2000;20:1155-1155.

29.

Fuster V , Steele PM , Edwards WD , et al. Primary pulmonary hypertension: Natural history and the importance of thrombosis. Circulation 1984;70:580-580.

30.

Schamroth CL , Sareli P , Pocock WA , et al. Pulmonary arterial thrombosis in secundum atrial septal defect. Am J Cardiol 1987;60:1152-1152.

31.

Niwa K , Perloff JK , Kaplan S , et al. Eisenmenger syndrome in adults: Ventricular septal defect, truncus arteriosus, univentricular heart. J Am Coll Cardiol 1999;34:232-232.