Age-Dependent Likelihood of In Situ Thrombosis in Secondary Pulmonary Hypertension

Abstract

Pulmonary arterial thrombosis (PAT) may complicate the clinical course of pulmonary hypertension associated with congenital heart disease (so-called Eisenmenger syndrome, ES). In this study, variables were sought that could represent risk factors for the occurrence of this complication. Twenty patients aged 11 to 53 (median, 33) years were studied. The presence of PAT (spiral computed tomography angiography) was correlated with age, gender group, PAP, hematocrit, peripheral oxygen saturation (SpO₂), and plasma levels of endothelial and coagulation dysfunction markers: von Willebrand factor antigen (vWF: Ag), tissue plasminogen activator (t-PA), and D-dimer (enzyme immunoassay). Patients were classified according to the presence (group 1, N=7), or absence (group 2, N=13) of PAT. Group 1 patients were older (42±8 vs. 27±10 years in group 2, p=0.0051), had lower SpO₂ (82±7% vs. 89±6% in group 2, p=0.0462) and increased D-dimer levels (637 vs. 149 ng/mL in group 2, median values, p=0.0235). A trend was observed toward an increase in vWF: Ag (125±29 vs. 103±18 U/dL in group 2, p=0.0789) and t-PA (15.7 vs. 9.4 ng/mL in group 2, median values, p=0.0689). Age was the main variable influencing the occurrence of PAT in multivariate analysis (p=0.0026), with odds ratio of 1.204 per year. The age of 35 years was 86% sensitive and 85% specific for occurrence of PAT. Age correlated positively with t-PA (r=0.57, p=0.0111). Thus, PAT is highly prevalent in ES as an age-dependent event, probably associated with endothelial dysfunction. Prophylactic anticoagulation should be considered before the age of 30 years, in particular in subjects with low SpO₂ and increased D-dimer levels.

Keywords

Pulmonary hypertension Endothelial dysfunction Thrombosis Hypoxia Intravascular coagulation

References

Rabinovitch M. Pulmonary hypertension: Updating a mysterious disease. Cardiovasc Res 1997;34:268.

The International consortium , Lane KB , Machado RD , et al. Heterozygous germline mutations in a TGF-β receptor, BMPR2, are the cause of familial primary pulmonary hypertension. Nat Genet 2000;26:81.

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

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

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.

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

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

Lopes AA , Caramurú LH , Maeda NY . Endothelial dysfunction associated with chronic intravascular coagulation in secondary pulmonary hypertension. Clin Appl Thromb Hemost 2002;8:353.

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.

10.

Wagenvoort CA , Mulder GH . Thrombotic lesions in primary plexogenic arteriopathy. Chest 1993;103:844.

11.

Rosenzweig EB , Barst R. Eisenmenger’s syndrome: Current management. Prog Cardiovasc Dis 2002;45:129.

12.

Kidd L , Driscoll DJ , Gersony WM , et al. Second natural history study of congenital heart defects. Results of treatment of patients with ventricular septal defects. Circulation 1993;87(suppl):138.

13.

Saha A , Balakrishnan KG , Jaiswal PK , et al. Prognosis for patients with Eisenmenger syndrome of various aetiology. Int J Cardiol 1994;45:1999.

14.

Moser KM , Auger WR , Fedullo PF , et al. Chronic thromboembolic pulmonary hypertension: Clinical picture and surgical treatment. Eur Respir J 1992;5:334.

15.

Simonneau G , Azarian R , Brenot F , et al. Surgical management of unresolved pulmonary embolism. A personal series of 72 patients. Chest 1995;107:52S.

16.

Rich S , ed. Primary pulmonary hypertension. Executive Summary from the World Symposium. Primary Pulmonary Hypertension; France, 1998. [WHO web site]. Available at: www.who.int/ncd/cvd/pph-htm%3E>1998.

17.

Maeda NY , Bydlowski SP , Lopes AAB . Platelet GP IIb/IIIa and non-receptor tyrosine kinases pp60 c-src and pp125FAK in patients with advanced pulmonary hypertension. Eur Heart J 2002;4:113.

18.

Caramurú LH , Soares RPS , Maeda NY , et al. Hypoxia and altered platelet behaviour influence von Willebrand factor multimeric composition in secondary pulmonary hypertension. Clin Appl Thromb Hemost 2003;9:251.

19.

Balabanian K , Foussat A , Dorfmüller P , et al. CX3 C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:1.

20.

Dorfmüller P , Zarka V , Durand-Gasselin I , et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:534.

21.

Coughlin SR . Protease-activated receptors in vascular biology. Thromb Haemost 2001;86:298.

22.

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.